2665Acute and Chronic Pancreatitis CHAPTER 348

in acute pancreatitis (Table 348-4). The events that initiate and then

perpetuate the inflammatory process in the pancreas are becoming

more clearly understood. Irrespective of the mechanism of injury,

it is becoming apparent that stellate cell activation leads to cytokine

expression and production of extracellular matrix proteins that contribute to acute and chronic inflammation and collagen deposition in

the pancreas. This condition is defined by the presence of histologic

abnormalities, including chronic inflammation, fibrosis, and progressive destruction (atrophy) of both exocrine and endocrine tissue. A

number of etiologies have been associated with chronic pancreatitis

resulting in the cardinal manifestations of the disease such as abdominal

pain, steatorrhea, weight loss, diabetes mellitus, and, less commonly,

pancreatic cancer (Table 348-5).

Even in individuals in whom alcohol is believed to be the primary

cause of chronic pancreatitis, other factors are likely required for the

development and progression of disease, which explains why not all

heavy consumers of alcohol develop pancreatic disease. There is also a

strong association between smoking and chronic pancreatitis. Cigarette

smoke leads to an increased susceptibility to pancreatic autodigestion

and predisposes to dysregulation of duct cell CFTR function. Smoking

is an independent, dose-dependent risk factor for chronic pancreatitis

and recurrent acute pancreatitis. Both continued alcohol and smoking

exposure are associated with disease progression, including pancreatic

fibrosis and calcifications.

Characterization of pancreatic stellate cells (PSCs) has added insight

into the underlying cellular responses behind development of chronic

pancreatitis. Specifically, PSCs are believed to play a role in maintaining

normal pancreatic architecture that shifts toward fibrogenesis in those

who develop chronic pancreatitis. It is believed that alcohol or additional stimuli lead to matrix metalloproteinase–mediated destruction

of normal collagen in pancreatic parenchyma, which later allows for

pancreatic remodeling. Proinflammatory cytokines, tumor necrosis

factor α (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6), as well

as oxidant complexes, can induce PSC activity with subsequent new

collagen synthesis. In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor

β (TGF-β)–mediated self-activating autocrine pathways that may

explain disease progression in chronic pancreatitis even after removal

of noxious stimuli.

■ ETIOLOGIC CONSIDERATIONS

Among adults in the United States, alcoholism is the most common

cause of clinically apparent chronic pancreatitis, whereas cystic fibrosis

is the most frequent cause in children. As many as 25% of adults in

the United States with chronic pancreatitis have the idiopathic form,

including a subset of patients who do not develop clinical manifestations until later in life (idiopathic late-onset chronic pancreatitis).

Recent investigations have indicated that up to 15% of patients with

chronic pancreatitis previously classified as having idiopathic pancreatitis may have an underlying genetic predisposition (Table 348-5).

The prototypical genetic defect was identified in the cationic

trypsinogen gene (PRSS1) by studying several large families with

chronic pancreatitis. Additional pathogenic and nonpathogenic mutations have been identified in this gene. The defect prevents the destruction of prematurely activated trypsin and allows it to be resistant to the

intracellular protective effect of trypsin inhibitor. It is hypothesized

that this continual activation of digestive enzymes within the gland

leads to acute injury and, finally, chronic pancreatitis. Since the initial

discovery of the PRSS1 mutation defect, other genetic disease modifiers

have been identified (Table 348-5).

The CFTR gene functions as a cyclic AMP–regulated chloride

channel. In patients with cystic fibrosis, the high concentration of

macromolecules can block the pancreatic ducts. It must be appreciated, however, that there is a great deal of heterogeneity in relationship

to the CFTR gene defect. More than 1700 putative mutations of the

CFTR gene have been identified. Attempts to elucidate the relationship

between the genotype and pancreatic manifestations have been hampered by the large number and different classes of CFTR mutations.

The ability to detect CFTR mutations has led to the recognition that

the clinical spectrum of the disease is broader than previously thought.

Two studies have clarified the association between mutations of the

CFTR gene and another monosymptomatic form of cystic fibrosis (i.e.,

chronic pancreatitis). It is estimated that in patients with idiopathic

pancreatitis, the frequency of a single CFTR mutation is 11 times the

expected frequency and the frequency of two mutant alleles is 80 times

the expected frequency. In these studies, patients were adults when the

diagnosis of pancreatitis was made; none had any clinical evidence of

pulmonary disease, and sweat test results were not diagnostic of cystic

fibrosis. The prevalence of such mutations is unclear, and further studies are needed. In addition, the therapeutic and prognostic implication

of these findings with respect to managing pancreatitis remains to be

determined. CFTR mutations are common in the general population,

so it is unclear whether the CFTR mutation alone can lead to pancreatitis as an autosomal recessive disease. A study evaluated 39 patients

with idiopathic chronic pancreatitis to assess the risk associated with

these mutations. Patients with two CFTR mutations (compound heterozygotes) demonstrated CFTR function at a level between that seen

in typical cystic fibrosis and cystic fibrosis carriers and had a fortyfold

increased risk of pancreatitis. The presence of a separate genetic mutation (N34S SPINK1) increased the risk twentyfold. A combination of

two CFTR mutations and an N34S SPINK1 mutation increased the risk

of pancreatitis 900-fold. Knowledge of the genetic defects and downstream alterations in protein expression has led to the development of

novel therapies in children with cystic fibrosis that potentiate the CFTR

channel, resulting in improvement in lung function, quality of life, and

weight gain. Some studies have shown that use of CFTR modulators

TABLE 348-5 Classification of Chronic Pancreatitis: The TIGAR-O

System

Toxic-metabolic

Alcoholic

Tobacco smoking

Hypercalcemia

Hyperlipidemia (hypertriglyceridemia)

Chronic renal failure

Idiopathic

Early onset

Late onset

Tropical

Genetic

Cationic trypsinogen (PRSS1)

Cystic fibrosis transmembrane conductance regulator gene (CFTR)

a

Calcium-sensing receptor (CASR)

a

Chymotrypsin C gene (CTRC)

a

Pancreatic secretory trypsin inhibitor gene (SPINK1)

a

Autoimmune

Type 1 autoimmune pancreatitis (associated with IgG4-related disease)

Type 2 autoimmune pancreatitis (idiopathic duct-centric chronic pancreatitis)

Recurrent and severe acute pancreatitis

Postnecrotic (severe acute pancreatitis)

Recurrent acute pancreatitis

Vascular diseases/ischemia

Radiation induced

Obstructive

Pancreas divisuma

Duct obstruction (e.g., tumor)

Preampullary duodenal wall cysts

Posttraumatic pancreatic duct strictures

a

These conditions are believed to be disease modifiers that require additional

factors to cause chronic pancreatitis.

Abbreviations: TIGAR-O, toxic-metabolic, idiopathic, genetic, autoimmune, recurrent

and severe acute pancreatitis, obstructive.

2666 PART 10 Disorders of the Gastrointestinal System

may reduce the frequency of acute pancreatitis in heterozygous carriers. Table 348-5 lists other recognized causes of chronic pancreatitis.

■ AUTOIMMUNE PANCREATITIS (TABLE 348-6)

Autoimmune pancreatitis (AIP) refers to a form of chronic pancreatitis with distinct histopathology and several unique differences in

the clinical phenotype. Currently, two subtypes of AIP are recognized,

type 1 AIP and idiopathic duct-centric chronic pancreatitis (IDCP,

also referred to as type 2 AIP). Type 1 AIP is identified as the pancreatic manifestation of a multiorgan syndrome currently referred to as

IgG4-related disease (Chap. 368). The characteristic histopathologic

findings of type 1 AIP include lymphoplasmacytic infiltrate, storiform

fibrosis, and abundant IgG4 cells. IDCP is histologically defined by

the presence of granulocytic infiltration of the duct wall (termed a

granulocytic epithelial lesion [GEL]) but without IgG4-positive cells.

Type 1 AIP is often associated with involvement of other organs in

the setting of IgG4-related disease, including bilateral submandibular

gland enlargement, characteristic renal lesions, retroperitoneal fibrosis,

and stricturing of the suprapancreatic biliary tree. In contrast, IDCP is

a pancreas-specific disorder that is associated with inflammatory bowel

disease in ~10% of patients. AIP is not a common cause of idiopathic

recurrent acute pancreatitis.

Jaundice, weight loss, and new-onset diabetes are the most common

presenting symptoms. Elevated serum IgG4 levels are supportive of the

diagnosis (elevated in two-thirds of patients with type 1 AIP) but have

a low positive predictive value when used in isolation of other clinical

findings. CT imaging demonstrates abnormalities in the majority of

patients with either diffuse or focal enlargement during active disease,

unless the gland is atrophic due to previous disease (Fig. 348-3). The

presence of an inflammatory rim, termed a capsule sign, is highly

specific (but not sensitive) for AIP. ERCP or MRCP reveals strictures

in the bile duct in more than one-third of patients with AIP, including

some patients with isolated intrahepatic bile duct strictures (type 1

AIP only), which can mimic primary sclerosing cholangitis, and is

referred to as IgG4-related sclerosing cholangitis (previously termed

IgG4-associated cholangitis).

The Mayo Clinic HISORt criteria provide a helpful mnemonic

to remember the key diagnostic features of this disease, including

(1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels);

(4) other organ involvement; and (5) response to glucocorticoid

therapy. These diagnostic criteria have been harmonized with those

from other countries to develop the International Consensus Diagnostic Criteria for AIP, which are the most widely utilized criteria. Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the

size of the pancreas, and reversing histopathologic features in patients

with AIP. Patients typically respond dramatically to glucocorticoid

therapy within a 2- to 4-week period. Prednisone is usually administered at an initial dose of 40 mg/d for 4 weeks followed by a taper of the

daily dosage by 5 mg per week based on monitoring of clinical parameters. Relief of symptoms, liver biochemistries, and abnormal imaging

of the pancreas and bile ducts are followed to assess for treatment

response. A poor response to glucocorticoids should raise suspicion

of an alternate diagnosis, such as pancreatic cancer. A recent multicenter international study examined >1000 patients with AIP. Clinical

remission was achieved in 99% of type 1 AIP and 92% of type 2 AIP

patients with steroids. However, disease relapse occurred in 31 and 9%

of patients with type 1 and type 2 AIP, respectively. Patients with

multiple relapses may be managed with an immunomodulator (e.g.,

azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or B-cell

depletion therapy (e.g., rituximab). The appearance of interval cancers

following a diagnosis of AIP is uncommon.

Clinical Features of Chronic Pancreatitis Patients with chronic

pancreatitis primarily seek medical attention due to abdominal pain or

symptoms of maldigestion. The abdominal pain may be quite variable in location, severity, and frequency. The pain can be constant or

TABLE 348-6 Comparison of the Autoimmune Pancreatitis (AIP)

Subtypes

TYPE 1 AIP TYPE 2 AIP

Age at diagnosis, mean Seventh decade Fifth decade

Male sex 75% 50%

Serum IgG4 elevation ~66% ~25%

Other organ involvement 50% Noa

Histologic findings:

Lymphoplasmacytic

Infiltration

++ ++

Periductal inflammation ++ ++

Storiform fibrosis ++ +

Obliterative phlebitis ++ +

Granulocytic epithelial

lesion (GEL)

– +++

IgG4 tissue staining Abundant

(≥10 cells/hpf)

Scant

(<10 cells/hpf)

Response to steroids ~100% ~100%

Risk for relapse High (20–60%) Low (<10%)

Associated with IgG4-RD Yes No

a

Inflammatory bowel disease is seen in ~10–20% of patients with idiopathic ductcentric chronic pancreatitis but may also occur in type 1 AIP.

Abbreviation: IgG4-RD, IgG4-related disease.

Source: Reproduced with permission from PA Hart: Reviews in basic and clinical

gastroenterology and hepatology. Gastroenterology 149:39, 2015.

A B

FIGURE 348-3 Imaging features of the pancreatic parenchyma in a patient with type 1 autoimmune pancreatitis on computed tomography (CT). A. Contrast-enhanced CT

scan of the abdomen demonstrates diffuse pancreatic enlargement and a hypoechoic rim (capsule sign) in a patient who presented with jaundice. The serum IgG4 level

was elevated to 942 mg/dL (reference range 4–86 mg/dL), so the patient was diagnosed with definitive type 1 autoimmune pancreatitis. B. Contrast-enhanced CT scan of the

abdomen following a treatment course with high-dose steroids demonstrates return to normal size of the pancreas, reappearance of normal lobulations along the margin,

and absence of the hypoechoic rim.

2667Acute and Chronic Pancreatitis CHAPTER 348

intermittent with pain-free intervals. Eating may exacerbate the pain,

leading to a fear of eating with consequent weight loss. The spectrum of

abdominal pain ranges from mild to quite severe, with narcotic dependence as a frequent consequence. There is often a disparity between

the reported severity of abdominal pain and the physical findings,

which primarily consist of nonfocal abdominal tenderness. Patients

with chronic abdominal pain may or may not experience symptoms

of maldigestion, such as chronic diarrhea, steatorrhea, and/or weight

loss. Fat-soluble vitamin deficiencies are increasingly recognized.

Importantly, there is an exceedingly high prevalence of metabolic bone

disease in chronic pancreatitis, with ~65% of patients having either

osteopenia or osteoporosis. Patients with chronic pancreatitis have

impaired quality of life and develop significant morbidity, requiring

frequent use of health care resources.

The diagnosis of early or mild chronic pancreatitis can be challenging because there is no accurate biomarker for the disease. In contrast

to acute pancreatitis, the serum amylase and lipase levels are usually

not strikingly elevated in chronic pancreatitis. Rather, low serum pancreatic enzyme levels are moderately specific for a diagnosis of chronic

pancreatitis but have poor sensitivity. Elevation of serum bilirubin and

alkaline phosphatase may indicate cholestasis secondary to common

bile duct stricture caused by chronic inflammation or fibrosis. The

cumulative prevalence of exocrine pancreatic insufficiency is >80%.

The presence of overt steatorrhea in a patient with chronic pancreatitis is highly suggestive of this complication. However, in those with

milder symptoms, additional testing, such as a random fecal elastase-1

level (on a formed stool specimen) may be needed to confirm the

diagnosis of exocrine pancreatic insufficiency. The radiographic

evaluation of a patient with suspected chronic pancreatitis usually proceeds from a noninvasive to more invasive approach. Abdominal CT

imaging (Fig. 348-4) is the initial modality of choice, followed by MRI,

endoscopic ultrasound, and pancreas function testing. In addition to

excluding a pseudocyst and pancreatic cancer, CT imaging may show

calcifications, dilated pancreatic or biliary ducts, or an atrophic pancreas. Although abdominal CT scanning and MRCP greatly aid in the

diagnosis of pancreatic disease, the diagnostic test with the best sensitivity is the hormone stimulation test using secretin. The secretin test

becomes abnormal when ≥60% of the pancreatic exocrine function has

been lost. This usually correlates well with the onset of chronic abdominal pain. The role of endoscopic ultrasonography (EUS) in diagnosing

early chronic pancreatitis is still evolving. A total of nine endosonographic features have been described in chronic pancreatitis. The

presence of five or more features is considered diagnostic of chronic

pancreatitis. EUS is not a specific enough test for detecting early

chronic pancreatitis alone (Chap. 347) and may show positive features

in patients with diabetes, patients with a history of cigarette smoking,

or even in normal aging individuals. Recent data suggest that EUS can

be combined with endoscopic pancreatic function testing (EUS-ePFT)

during a single endoscopy to screen for chronic pancreatitis in patients

with chronic abdominal pain. Diffuse calcifications noted on plain film

of the abdomen usually indicate significant damage to the pancreas and

are pathognomic for chronic pancreatitis. Although alcohol is by far

the most common cause of pancreatic calcification, such calcification

may also be noted in hereditary pancreatitis, posttraumatic pancreatitis, idiopathic chronic pancreatitis, and tropical pancreatitis.

Complications of Chronic Pancreatitis There are a number

of disease-related complications from chronic pancreatitis in addition to the aforementioned abdominal pain and exocrine pancreatic insufficiency (Table 348-7). The lifetime prevalence of chronic

A B

C D

FIGURE 348-4 Distribution of imaging features of chronic pancreatitis on computed tomography (CT). Distinct features of chronic pancreatitis are seen on selected

images from contrast-enhanced CT scans of the abdomen from four unique patients, including the following. A. Numerous punctate calcifications involving the pancreatic

parenchyma in the head and body. B. A moderate-sized calculus visualized in the pancreatic duct with associated ductal dilation. C. Significant pancreatic duct dilation

and adjacent parenchymal atrophy secondary to a pancreatic duct stricture (which is not well seen on this scan). D. A large unilocular, encapsulated cyst in the tail of the

pancreas consistent with a pseudocyst from prior pancreatitis. Note adjacent pancreatic parenchymal atrophy.

2668 PART 10 Disorders of the Gastrointestinal System

pancreatitis–related diabetes exceeds 80%. Although most patients

develop hyperglycemia due to insulin deficiency caused by loss of

islet cells, diabetic ketoacidosis and diabetic coma are uncommon.

Likewise, end-organ damage (retinopathy, neuropathy, nephropathy)

is also uncommon. Nondiabetic retinopathy may be due to vitamin A

and/or zinc deficiency. Osteoporosis and osteopenia are increasingly

recognized in chronic pancreatitis and likely related to a combination

of shared risk factors (e.g., alcohol use, cigarette smoking), vitamin D

deficiency, and detrimental effects on the bone from chronic inflammation. Gastrointestinal bleeding may occur from peptic ulceration,

gastritis, a pseudocyst eroding into the duodenum, arterial bleeding

into the pancreatic duct (hemosuccus pancreaticus), or ruptured

varices secondary to splenic vein thrombosis. Jaundice, cholestasis, and

biliary cirrhosis may occur from the chronic inflammatory reaction

around the intrapancreatic portion of the common bile duct. Twenty

years after the diagnosis of chronic calcific pancreatitis, the cumulative

risk of pancreatic cancer is 4%. Patients with hereditary PRSS1 or tropical pancreatitis have an increased risk for pancreatic cancer compared

to other forms of chronic pancreatitis.

TREATMENT

Chronic Pancreatitis

There are currently no therapies to reverse or delay the disease

progression of chronic pancreatitis, so management is primarily focused on screening for and management of disease-related

complications.

STEATORRHEA

The treatment of steatorrhea with pancreatic enzyme replacement

therapy is conceptually straightforward, yet complete correction of

steatorrhea is uncommon. Enzyme therapy usually brings diarrhea

under control and restores absorption of fat to an acceptable level

and affects weight gain. Thus, pancreatic enzyme replacement is the

cornerstone of therapy. In treating steatorrhea, it is important to

use a potent pancreatic formulation that will deliver sufficient lipase

into the duodenum to correct maldigestion and decrease steatorrhea. For adult patients with exocrine pancreatic insufficiency, it is

generally recommended to start at a dosage of 25,000–50,000 units

of lipase taken during each meal; however, the dose may need to be

increased up to 100,000 units of lipase depending on the response

in symptoms, nutritional parameters, and/or pancreas function

test results. Additionally, some may require acid suppression with

proton pump inhibitors to optimize the response to pancreatic

enzymes. Monitoring nutritional parameters such as fat-soluble

vitamins, zinc levels, body weight, and periodic bone mineral density measurement should be considered.

ABDOMINAL PAIN

The management of pain in patients with chronic pancreatitis is

challenging due to the complex mechanisms of pancreatitis-related

pain. Recent meta-analyses have shown no consistent benefit of

enzyme therapy at reducing pain in chronic pancreatitis. Pain relief

experienced by patients treated with pancreatic enzymes may be

due to improvements in the dyspepsia from maldigestion. One

short-term randomized trial showed that pregabalin could decrease

pain in chronic pancreatitis and lower pain medication requirement. Other studies using antioxidants have yielded mixed results.

Endoscopic treatment of chronic pancreatitis pain may involve

sphincterotomy, pancreatic duct stenting, stone extraction, and

drainage of a pancreatic pseudocyst. Therapy directed to the

pancreatic duct would seem to be most appropriate in the setting of

a dominant stricture, especially if there is an obstructing intraductal stone. The use of endoscopic stenting for patients with chronic

pain, but without a dominant stricture, has not been subjected to

controlled trials. It is now appreciated that significant complications can occur from stenting (e.g., stent migration, stent occlusion,

and stent-induced pancreatic duct strictures). Recent guidelines

recommend considering celiac plexus block for treatment of pain

in chronic pancreatitis, but recommendations were conditional

with very low quality of evidence. Celiac plexus block has not been

rigorously studied for chronic pancreatitis and does not provide

durable pain relief. It can provide relive in some selected patients,

but the a priori identification of those who will respond is difficult.

In patients with pancreatic duct dilation, ductal decompression

with surgical therapy has been the therapy of choice. Among such

patients, 80% seem to obtain immediate relief; however, at the end

of 3 years, one-half of the patients have recurrence of pain. Two

randomized prospective trials comparing endoscopic to surgical

therapy for chronic pancreatitis demonstrated that surgical therapy

was superior to endoscopy at decreasing pain and improving quality

of life in selected patients with dilated ducts and abdominal pain.

This would suggest that chronic pancreatitis patients with dilated

ducts and pain should be considered for surgical intervention.

The role of preoperative stenting prior to surgery as a predictor of

response has yet to be proven.

Total pancreatectomy with or without autologous islet cell transplantation has been used in highly selected patients with chronic

pancreatitis and abdominal pain refractory to conventional therapy.

However, some patients will continue to have pain postoperatively,

illustrating the complex nature of pain in patients with chronic pancreatitis. Patients who benefit most from total pancreatectomy have

a shorter duration of symptoms and lower pain medication requirements. The role of this procedure remains to be fully defined but

may be an option in lieu of ductal decompression surgery or partial

pancreatic resection in patients with intractable, painful, small-duct

disease or hereditary pancreatitis and particularly as the standard

surgical procedures tend to decrease islet cell yield.

■ HEREDITARY PANCREATITIS

Hereditary pancreatitis (PRSS1) is a rare form of pancreatitis with early

age of onset that is typically associated with familial aggregation of

cases. A genome-wide search using genetic linkage analysis identified

the hereditary pancreatitis gene on chromosome 7. Mutations in ion

codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene

(PRSS1) cause an autosomal dominant form of pancreatitis. The codon

122 mutations lead to a substitution of the corresponding arginine

with another amino acid, usually histidine. This substitution, when it

occurs, eliminates a fail-safe trypsin self-destruction site necessary to

eliminate trypsin that is prematurely activated within the acinar cell.

These patients have recurring episodes of acute pancreatitis. Patients

frequently develop pancreatic calcification, diabetes mellitus, and

steatorrhea; in addition, they have an increased incidence of pancreatic

cancer with a cumulative incidence of ~10%. A previous natural history

study of hereditary pancreatitis in >200 patients from France reported

that abdominal pain started in childhood at age 10 years, steatorrhea

developed at age 29 years, diabetes at age 38 years, and pancreatic cancer at age 55 years. Abdominal complaints in relatives of patients with

hereditary pancreatitis should raise the question of pancreatic disease.

■ PANCREATIC ENDOCRINE TUMORS

Pancreatic endocrine tumors are discussed in Chap. 84.

OTHER CONDITIONS

■ ANNULAR PANCREAS

When the ventral pancreatic anlage fails to migrate correctly to make

contact with the dorsal anlage, the result may be a ring of pancreatic tissue encircling the duodenum. Such an annular pancreas may

cause intestinal obstruction in the neonate or the adult. Symptoms of

TABLE 348-7 Complications of Chronic Pancreatitis

Chronic abdominal pain

Exocrine pancreatic insufficiency

Diabetes mellitus

Splanchnic venous thrombosis

Metabolic bone disease (osteoporosis)

Biliary stricture and/or biliary cirrhosis

Pancreatic duct stricture

Pseudocyst

Pancreatic cancer

2669Acute and Chronic Pancreatitis CHAPTER 348

postprandial fullness, epigastric pain, nausea, and vomiting may be

present for years before the diagnosis is entertained. The radiographic

findings are symmetric dilation of the proximal duodenum with bulging of the recesses on either side of the annular band, effacement but

not destruction of the duodenal mucosa, accentuation of the findings

in the right anterior oblique position, and lack of change on repeated

examinations. The differential diagnosis should include duodenal

webs, tumors of the pancreas or duodenum, duodenal ulcer, regional

enteritis, and adhesions. Patients with annular pancreas have an

increased incidence of pancreatitis and peptic ulcer. Because of these

and other potential complications, the treatment is surgical even if the

condition has been present for years. Retrocolic duodenojejunostomy

is the procedure of choice, although some surgeons advocate Billroth II

gastrectomy, gastroenterostomy, and vagotomy.

■ PANCREAS DIVISUM

Pancreas divisum is present in 7–10% of the population and occurs

when the embryologic ventral and dorsal pancreatic anlagen fail to

fuse, so that pancreatic drainage is accomplished mainly through

the accessory minor papilla. Pancreas divisum is the most common

congenital anatomic variant of the human pancreas. Current evidence

indicates that this anomaly does not predispose to the development

of pancreatitis in the majority of patients who harbor it. However, the

combination of pancreas divisum and a small accessory orifice could

result in dorsal duct obstruction. The challenge is to identify this subset of patients with dorsal duct pathology. Cannulation of the dorsal

duct by ERCP is technically challenging and associated with a very

high risk of post-ERCP pancreatitis, so patients with pancreatitis and

pancreas divisum should likely be treated with conservative measures.

In many of these patients, pancreatitis is idiopathic and unrelated to

the pancreas divisum. Endoscopic or surgical intervention is indicated

only if pancreatitis recurs and no other cause can be found. It should

be stressed that the ERCP/MRCP appearance of pancreas divisum (i.e.,

a small-caliber ventral duct with an arborizing pattern) may be mistaken as representing an obstructed main pancreatic duct secondary

to a mass lesion.

■ MACROAMYLASEMIA

In macroamylasemia, amylase circulates in the blood in a polymer

form too large to be easily excreted by the kidney. Patients with this

condition demonstrate an elevated serum amylase value and a low urinary amylase value. The presence of macroamylase can be documented

by chromatography of the serum. The prevalence of macroamylasemia

is 1.5% of the nonalcoholic general adult hospital population. Usually,

macroamylasemia is an incidental finding and is not related to disease

of the pancreas or other organs. Macrolipasemia has now been documented in patients with cirrhosis or non-Hodgkin’s lymphoma. In these

patients, the pancreas appeared normal on ultrasound and CT examination. Lipase was shown to be complexed with immunoglobulin A.

Thus, the possibility of both macroamylasemia and macrolipasemia

should be considered in patients with elevated blood levels of these

enzymes.

Acknowledgment

This chapter represents a revised version of chapters by Drs. Norton J.

Greenberger (deceased), Phillip P. Toskes (deceased), Peter A. Banks, and

Bechien Wu that were in previous editions of Harrison’s.

■ FURTHER READING

Crockett SD et al: American Gastroenterological Association Institute guideline on initial management of acute pancreatitis. Gastroenterology 154:1096, 2018.

Forsmark CE et al: Acute pancreatitis. N Engl J Med 375:1972, 2016.

Gardner TB et al: ACG clinical guideline: Chronic pancreatitis. Am J

Gastroenterol 115:322, 2020.

Hart PA, Conwell DL: Chronic pancreatitis: Managing a difficult

disease. Am J Gastroenterol 115:49, 2020.

Hart PA et al: Recent advances in autoimmune pancreatitis. Gastroenterology 149:39, 2015.

Petrov MS, Yadav D: Global epidemiology and holistic prevention of

pancreatitis. Nat Rev Gastroenterol Hepatol 16:175, 2019.

Yadav D, Lowenfels AB: The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144:1252, 2013.

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Section 1 The Immune System in Health

and Disease

Immune-Mediated, Inflammatory, and Rheumatologic Disorders PART 11

349 Introduction to the

Immune System

Barton F. Haynes, Kelly A. Soderberg,

Anthony S. Fauci

■ DEFINITIONS • Adaptive immune system—recently evolved system of immune

responses mediated by T and B lymphocytes. Immune responses by

these cells are based on specific antigen recognition by clonotypic

receptors that are products of genes that rearrange during development and throughout the life of the organism. Additional cells of the

adaptive immune system include various types of antigen-presenting

cells (APCs).

• Antibody—B cell–produced molecules encoded by genes that rearrange during B-cell development consisting of immunoglobulin

heavy and light chains that together form the central component

of the B-cell receptor (BCR) for antigen. Antibody can exist as B

cell–surface antigen-recognition molecules or as secreted molecules

in plasma and other body fluids.

• Antigens—foreign or self-molecules that are recognized by the adaptive and innate immune systems resulting in immune cell triggering,

T-cell activation, and/or B-cell antibody production.

• Antimicrobial peptides—small peptides <100 amino acids in length

that are produced by cells of the innate immune system and have

anti-infectious agent activity.

• Apoptosis—the process of programmed cell death whereby signaling through various “death receptors” on the surface of cells (e.g.,

tumor necrosis factor [TNF] receptors, CD95) leads to a signaling

cascade that involves activation of the caspase family of molecules

and leads to DNA cleavage and cell death. Apoptosis, which does

not lead to induction of inordinate inflammation, is to be contrasted with cell necrosis, which does lead to induction of inflammatory responses.

• Autoimmune diseases—diseases such as systemic lupus erythematosus and rheumatoid arthritis in which cells of the adaptive immune

system such as autoreactive T and B cells become overreactive and

produce self-reactive T-cell and antibody responses.

• Autoinflammatory diseases—hereditary disorders such as hereditary

periodic fevers (HPFs) characterized by recurrent episodes of severe

inflammation and fever due to mutations in controls of the innate

inflammatory response, i.e., the inflammasome (see below and

Table 349-5). Patients with HPFs also have rashes, serosal and joint

inflammation, and some can have neurologic symptoms. Autoinflammatory diseases are different from autoimmune diseases in that

evidence for activation of adaptive immune cells such as autoreactive B cells is not present.

• Autophagy—lysosomal degradation pathway mechanism of cells to

dispose of intracellular debris and damaged organelles. Autophagy

by cells of the innate immune system is used to control intracellular infectious agents such as mycobacteria, in part by initiation of

phagosome maturation and enhancing major histocompatibility

complex (MHC) class II antigen presentation to CD4 T cells.

• B-cell receptor for antigen—complex of surface molecules that

rearrange during postnatal B-cell development, made up of surface

immunoglobulin (Ig) and associated Ig αβ chain molecules that

recognize nominal antigen via Ig heavy- and light-chain variable

regions, and signal the B cell to terminally differentiate to make

antigen-specific antibody.

• B lymphocytes—bone marrow–derived or bursal-equivalent lymphocytes that express surface immunoglobulin (the BCR for antigen) and secrete specific antibody after interaction with antigen.

• B regulatory cells—a population of suppressive B cells that aid in the

inhibition of inflammation through the release of cytokines such as

interleukin (IL) 10.

• CD classification of human lymphocyte differentiation antigens—the

development of monoclonal antibody technology led to the discovery of a large number of new leukocyte surface molecules. In 1982,

the First International Workshop on Leukocyte Differentiation

Antigens was held to establish a nomenclature for cell-surface molecules of human leukocytes. From this and subsequent leukocyte

differentiation workshops has come the cluster of differentiation

(CD) classification of leukocyte antigens.

• CD4 T cell—T lymphocyte subset that participates in adaptive

immunity and helps B cells make antibody.

• CD8 T cell—cytotoxic T lymphocyte subset that destroys tumor cells

and cells infected with pathogens.

• Chemokines—soluble molecules that direct and determine immune

cell movement and circulation pathways.

• Complement—cascading series of plasma enzymes and effector

proteins that function to lyse pathogens and/or target them to be

phagocytized by neutrophils and monocyte/macrophage lineage

cells of the reticuloendothelial system.

• Co-stimulatory molecules—molecules of APCs (such as B7-1 and

B7-2 or CD40) that lead to T-cell activation when bound by ligands

on activated T cells (such as CD28 or CD40 ligand).

• Crystallopathies—nanoparticle- or microparticle-sized deposits of

crystals, misfolded proteins, or airborne particulate matter that can

stimulate the inflammasome and initiate inflammation and tissue

damage.

• Cytokines—soluble proteins that interact with specific cellular receptors that are involved in the regulation of the growth and activation

of immune cells and mediate normal or pathologic inflammatory

and immune responses.

• Dendritic cells—myeloid and/or lymphoid lineage APCs of the

adaptive immune system. Immature dendritic cells (DCs), or DC

precursors, are key components of the innate immune system by

responding to infections with production of high levels of cytokines.

DCs are key initiators both of innate immune responses via cytokine

production and of adaptive immune responses via presentation of

antigen to T lymphocytes.

• Ig Fc receptors—receptors found on the surface of certain cells

including B cells, natural killer (NK) cells, macrophages, neutrophils, and mast cells. Fc receptors bind to antibodies that have

attached to invading pathogen-infected cells. They stimulate cytotoxic cells to destroy microbe-infected cells through a mechanism

known as antibody-dependent cell-mediated cytotoxicity (ADCC).

Examples of important Fc receptors include CD16 (FcγRIIIa), CD23

(FcεR), CD32 (FcγRII), CD64 (FcγRI), and CD89 (FcαR).

• Inflammasome—large cytoplasmic complexes of intracellular proteins that link the sensing of microbial products and cellular stress

to the proteolytic activation of IL-1β and IL-18 inflammatory

cytokines. Activation of molecules in the inflammasome is a key

step in the response of the innate immune system for intracellular

recognition of microbial and other danger signals in both health and

pathologic states.

• Innate immune system—ancient immune recognition system of

host cells bearing germline-encoded pattern recognition receptors

(PRRs) that recognize pathogens and trigger a variety of mechanisms of pathogen elimination. Cells of the innate immune system

include NK cell lymphocytes, monocytes/macrophages, DCs, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells.

2672 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

• Innate lymphoid cells (ILCs)—lymphocytes that do not express the

type of diversified antigen receptors on T cell and B cells. ILC1s,

ILC2s, and ILC3s are tissue resident cells and functionally are analogous to CD4 TH1, TH2, and TH17 cells, respectively.

• Natural killer (NK) cells—a type of ILC that kills target cells expressing few or no human leukocyte antigen (HLA) class I molecules,

such as malignantly transformed cells and virally infected cells. NK

cells express receptors that inhibit killer cell function when selfMHC class I is present. Innate NK cells mirror the functions of CD8

cytotoxic T cells of the adaptive immune system.

• NK T cells—innate-like lymphocytes that use an invariant T-cell

receptor (TCR)-α chain combined with a limited set of TCR-β

chains and coexpress receptors commonly found on NK cells. NK T

cells recognize lipid antigens of bacterial, viral, fungal, and protozoal

infectious agents.

• Pathogen-associated molecular patterns (PAMPs)—invariant molecular structures expressed by large groups of microorganisms that

are recognized by host cellular PRRs in the mediation of innate

immunity.

• Pattern recognition receptors (PRR)—germline-encoded receptors

expressed by cells of the innate immune system that recognize

PAMPs.

• Polyreactive antibodies—low-affinity antibodies produced by B cells

that cross-react with multiple antigens and are available at the time

of infection to bind and coat invading pathogens and harness innate

responses to slow the infection until an adaptive high-affinity protective antibody response can be made.

• T lymphocytes—thymus-derived lymphocytes that mediate adaptive

cellular immune responses including T helper, T regulatory, and

cytotoxic T lymphocyte effector cell functions.

• T-cell exhaustion—state of T cells when the persistence of antigen

disrupts memory T-cell function, resulting in defects in memory

T-cell responses. Most frequently occurs in malignancies and in

chronic viral infections such as HIV-1 and hepatitis C.

• TCR for antigen—complex of surface molecules that rearrange

during postnatal T-cell development made up of clonotypic TCR-α

and -β chains that are associated with the CD3 complex composed

of invariant γ, δ, ε, ζ, and η chains. TCR-α and -β chains recognize

peptide fragments of protein antigen physically bound in APC MHC

class I or II molecules, leading to signaling via the CD3 complex to

mediate effector functions.

• T follicular helper T cells (Tfh)—CD4 T cells regulated by bcl-6 in

B-cell follicle germinal centers that produce IL-4 and IL-21 and

drive B-cell differentiation and affinity maturation in peripheral

lymphoid tissues such as lymph node and spleen.

• TH1 T cells—CD4 helper T-cell subset regulated by transcription

factor T-bet that produces interferon (IFN)-γ, IL-2, and TNF-β and

participates in cell-mediated immunity.

• TH2 T cells—CD4 helper T-cell subset regulated by transcription factors STAT6 and GATA3 that produces IL-4, IL-5, IL-6, IL-9, IL-10,

and IL-13 and regulates antibody and eosinophil responses.

• T regulatory cells (Treg)—CD4 and CD8 T cells regulated by the

transcription factor Foxp3 that play roles in modulating the immune

system to prevent deleterious immune activation. Expression of

Foxp3 is a defining Treg marker.

• TH9 T cells—CD4 T cells regulated by the transcription factor PU.1

that secrete IL-9 and enhance inflammation in atopic disease and

inflammatory bowel disease as well as mediate antitumor immunity.

• TH13 T cells—T follicular helper cells (Tfh) regulated by the GATA3

transcription factor that produce IL-4, IL-5, and IL-13. TH13 Tfh

induce high-affinity IgE antibody responses that cause anaphylactic

reactions to allergens.

• TH17 T cells—CD4 T cells regulated by the transcription factor

RORγt that secrete IL-17, IL-22, and IL-26 and play roles in autoimmune inflammatory disorders as well as defend against bacterial

and fungal pathogens.

• Tolerance—B- and T-cell nonresponsiveness to antigens that results

from encounter with foreign or self-antigens by B and T lymphocytes in the absence of expression of APC co-stimulatory

molecules. Tolerance to antigens may be induced and maintained

by multiple mechanisms either centrally (B-cell deletion in the

thymus for T cells or bone marrow for B cells) or peripherally (by

cell deletion or anergy at sites throughout the peripheral immune

system).

• Trained immunity—the epigenetic, transcriptional, and functional

reprogramming of innate immune cells to adapt to previous encounters with pathogens and respond to a second challenge in an altered

manner.

■ INTRODUCTION

The human immune system has evolved over millions of years from

both invertebrate and vertebrate organisms to develop sophisticated

defense mechanisms that protect the host from microbes and their

virulence factors. The normal immune system has three key properties:

a highly diverse repertoire of antigen receptors that enables recognition

of a nearly infinite range of pathogens; immune memory, to mount

rapid recall immune responses; and immunologic tolerance, to avoid

immune damage to normal self-tissues. From invertebrates, humans

have inherited the innate immune system, an ancient defense system

that uses germline-encoded proteins to recognize pathogens. Cells of

the innate immune system, such as macrophages, DCs, and NK lymphocytes, recognize PAMPs that are highly conserved among many

microbes and use a diverse set of PRR molecules. Important components of the recognition of microbes by the innate immune system

include recognition by germline-encoded host molecules, recognition

of key microbe virulence factors but not recognition of self-molecules,

and nonrecognition of benign foreign molecules or microbes. Upon

contact with pathogens, cells of the innate immune system may kill

pathogens directly or, in concert with DCs, activate a series of events

that both slow the infection and recruit the more recently evolved

arm of the human immune system, the adaptive immune system. In

addition, innate immune cells undergo epigenetic, transcriptional, and

functional changes that allow adapted (either enhanced or reduced)

innate cell responses to repeat encounters with pathogens, called

trained immunity.

Adaptive immunity is found only in vertebrates and is based on the

generation of antigen receptors on T and B lymphocytes by gene rearrangements, such that individual T or B cells express unique antigen

receptors on their surface capable of specifically recognizing diverse

antigens of infectious agents in the environment. Coupled with specific

recognition mechanisms that maintain tolerance (nonreactivity) to

self-antigens (Chap. 350), T and B lymphocytes bring both specificity

and immune memory to vertebrate host defenses.

This chapter describes the cellular components, key molecules

(Table 349-1), and mechanisms that make up the innate and adaptive

immune systems and describes how adaptive immunity is recruited to

the defense of the host by innate immune responses. An appreciation

of the cellular and molecular bases of innate and adaptive immune

responses is critical to understanding the pathogenesis of inflammatory, autoimmune, infectious, and immunodeficiency diseases, as

well as a wide range of diseases associated with inflammation such as

atherosclerotic cardiovascular disease and neurodegenerative diseases.

■ THE INNATE IMMUNE SYSTEM

All multicellular organisms, including humans, have developed the use

of surface and intracellular germline-encoded molecules that recognize

pathogens. Because of the myriad of human pathogens, host molecules

of the human innate immune system sense “danger signals” and either

recognize PAMPs, the common molecular structures shared by many

pathogens, or recognize host cell molecules produced in response to

infection such as heat shock proteins and fragments of the extracellular

matrix. PAMPs must be conserved structures vital to pathogen virulence

and survival, such as bacterial endotoxin, so that pathogens cannot

mutate molecules of PAMPs to evade human innate immune responses.

PRRs are host proteins of the innate immune system that recognize

PAMPs as host danger signal molecules (Tables 349-2 and 349-3).

Thus, recognition of pathogen molecules by hematopoietic and

Introduction to the Immune System

2673CHAPTER 349

TABLE 349-1 Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens

SURFACE ANTIGEN

(OTHER NAMES) FAMILY

MOLECULAR

MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION

CD1a (T6, HTA-1) Ig 49 CD, cortical thymocytes,

Langerhans type of DCs

TCRγδ T cells, NK T cells CD1 molecules present lipid antigens of

intracellular bacteria such as Mycobacterium

leprae and M. tuberculosis to TCRγδT cells or

NK T cells

CD1b Ig 45 CD, cortical thymocytes,

Langerhans type of DCs

TCRγδ T cells, NK T cells

CD1c Ig 43 DC, cortical thymocytes,

subset of B cells, Langerhans

type of DCs

TCRγδ T cells, NK T cells

CD1d Ig 37 Cortical thymocytes, intestinal

epithelium, Langerhans type

of DCs

TCRγδ T cells, NK T cells

CD2 (T12, LFA-2) Ig 50 T, NK CD58, CD48, CD59, CD15 Alternative T-cell activation, T-cell anergy,

T-cell cytokine production, T- or NK-mediated

cytolysis, T-cell apoptosis, cell adhesion

CD3 (T3, Leu-4) Ig γ:25–28, δ:21–28,

ε:20–25, η:21–22,

ζ:16

T, NK T Associates with the TCR T-cell activation and function; ζ is the signal

transduction component of the CD3 complex

CD4 (T4, Leu-3) Ig 55 T, myeloid MHC-II, HIV gp120, IL-16,

SABP

T-cell selection, T-cell activation, signal

transduction with p56lck, primary receptor for

HIV-1

CD7 (3A1, Leu-9) Ig 40 T, NK K-12 (CD7L) T- and NK-cell signal transduction and

regulation of IFN-γ, TNF-α production

CD8 (T8, Leu-2) Ig 34 T, subset of NK MHC-I T-cell selection, T-cell activation, signal

transduction with p56lck

CD14 (LPS-receptor) LRG 53–55 M, G (weak), not by myeloid

progenitors

Endotoxin

(lipopolysaccharide),

lipoteichoic acid, PI

TLR4 mediates with LPS and other PAMP

activation of innate immunity

CD16a (FcγRIIIa) Ig 50–80 NK, macrophages, neutrophils Fc portion of IgG Mediates phagocytosis and ADCC

CD19 B4 Ig 95 B (except plasma cells), FDC Not known Associates with CD21 and CD81 to form a

complex involved in signal transduction in B-cell

development, activation, and differentiation

CD20 (B1) Unassigned 33–37 B (except plasma cells) Not known Cell signaling, may be important for B-cell

activation and proliferation

CD21 (B2, CR2, EBV-R,

C3dR)

RCA 145 Mature B, FDC, subset of

thymocytes

C3d, C3dg, iC3b, CD23,

EBV

Associates with CD19 and CD81 to form a

complex involved in signal transduction

in B-cell development, activation, and

differentiation; Epstein-Barr virus receptor

CD22 (BL-CAM) Ig 130–140 Mature B CDw75 Cell adhesion, signaling through association

with p72sky, p53/56lyn, PI3 kinase, SHP1, fLCγ

CD23 (FcεRII, B6, Leu20, BLAST-2)

C-type lectin 45 B, M, FDC IgE, CD21, CD11b, CD11c Regulates IgE synthesis, cytokine release by

monocytes

CD28 Ig 44 T, plasma cells CD80, CD86 Co-stimulatory for T-cell activation; involved

in the decision between T-cell activation and

anergy

CD32a (FcγRIIa) Ig 40 NK, macrophages, neutrophils Fc portion of IgG Mediates phagocytosis and ADCC

CD40 TNFR 48–50 B, DC, EC, thymic epithelium,

MP, cancers

CD154 (CD40L) B-cell activation, proliferation, and

differentiation; formation of GCs; isotype

switching; rescue from apoptosis

CD45 (LCA, T200,

B220)

PTP 180, 200, 210, 220 All leukocytes Galectin-1, CD2, CD3, CD4 T and B activation, thymocyte development,

signal transduction, apoptosis

CD45RA PTP 210, 220 Subset T, medullary

thymocytes, “naive” T

Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing exon 4 (A),

restricted to a subset of T cells

CD45RB PTP 200, 210, 220 All leukocytes Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing exon 5 (B)

CD45RC PTP 210, 220 Subset T, medullary

thymocytes, “naive” T

Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing exon 6 (C),

restricted to a subset of T cells

CD45RO PTP 180 Subset T, cortical thymocytes,

“memory” T

Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing no differentially

spliced exons, restricted to a subset of T cells

CD64 (FcγRI) Ig 45–55 Macrophages and monocytes Fc portion of IgG Mediates phagocytosis and ADCC

CD80 (B7-1, BB1) Ig 60 Activated B and T, MP, DC CD28, CD152 (CTLA-4) Co-regulator of T-cell activation; signaling

through CD28 stimulates and through CD152

inhibits T-cell activation

CD86 (B7-2, B70) Ig 80 Subset B, DC, EC, activated T,

thymic epithelium

CD28, CD152 (CTLA-4) Co-regulator of T-cell activation; signaling

through CD28 stimulates and through CD152

inhibits T-cell activation

(Continued)

2674 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 349-2 Major Components of the Innate Immune System

Pattern recognition

receptors (PRRs)

Toll-like receptors (TLRs), C-type lectin receptors

(CLRs), retinoic acid–inducible gene (RIG)-1-like

receptors (RLRs), and NOD-like receptors (NLRs)

Antimicrobial peptides α-Defensins, β-defensins, cathelin, protegrin,

granulysin, histatin, secretory leukoprotease inhibitor,

and probiotics

Cells Macrophages, dendritic cells, innate lymphoid cells

(ILC1, ILC2, ILC3, NK cells, lymphoid tissue inducer

[LTi] cells), mucosal-associated invariant T (MAIT)

cells, NK-T cells, neutrophils, eosinophils, mast cells,

basophils, and epithelial cells

Complement

components

Classic and alternative complement pathway, and

proteins that bind complement components

Cytokines Autocrine, paracrine, endocrine cytokines that

mediate host defense and inflammation, as well

as recruit, direct, and regulate adaptive immune

responses

Abbreviation: NK, natural killer.

TABLE 349-1 Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens

SURFACE ANTIGEN

(OTHER NAMES) FAMILY

MOLECULAR

MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION

CD89 (FCαR) Ig 55–100 Neutrophils, eosinophils,

monocytes, and MP

Fc portion of IgG Mediates phagocytosis and ADCC of IgAcoated pathogens

CD95 (APO-1, Fas) TNFR 43 Activated T and B Fas ligand Mediates apoptosis

CD112 (nekton-2,

PVRL2)

Ig 62 Epithelial cells, endothelial

cells, other tissues

DNAM-1 (CD226), TIGIT T-cell activation (DNAM-1), T-cell inhibition

(TIGIT)

CD134 (OX40) TNFR 48 Activated T OX40L (CD252) T-cell survival, cytokine stimulation

CD137 (4-1BB) TNFR 19 Activated T, DCs, B, NK CD137L (41BBL) T-cell co-stimulation

CD155 (PVR) Ig 50–65 DCs, NK, epithelial cells TIGIT, CD96, DNAM-1 T-cell inhibition (TIGIT, CD96), T-cell activation

(DNAM-1)

CD223 (LAG-3) Ig 57 NK, B, activated T MHC class II T-cell inhibition

CD226 (DNAM-1) Ig 65 NK, monocytes, T CD112, CD155 T-cell activation (CD112), T-cell activation

(CD155)

CD252 (OX40L) TNFR 16–25 Antigen-presenting cells,

endothelial cells

OX40 T-cell survival, cytokine stimulation

CD272 (BTLA) Ig 16 Activated T HVEM T-cell inhibition

CD274 (PD-L1) Ig 40 T, NK, myeloid, B, tumor cells PD-1 (CD279) Inhibit TCR activation

CD278 (ICOS) Ig 55–60 Activated T ICOSL T-cell activation

CD357 (GTTR) TNFR 41 Activated T, Tregs GITRL T-cell activation

CD152 (CTLA-4) Ig 30–33 Activated T CD80, CD86 Inhibits T-cell proliferation

CD154 (CD40L) TNF 33 Activated CD4+ T, subset CD8+

T, NK, M, basophil

CD40 Co-stimulatory for T-cell activation, B-cell

proliferation and differentiation

CD279 (PD-1) Ig 50–55 B, T, Tfh PD-L1 (CD274), PD-L2

(CD273)

Inhibits T-cell proliferation

Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; BTLA, band T lymphocyte attenuators; CTLA, cytotoxic T lymphocyte–associated protein; DC,

dendritic cells; DNAM-1, DNAX accessory molecule-1; EBV, Epstein-Barr virus; EC, endothelial cells; ECM, extracellular matrix; Fcγ RIII, low-affinity IgG receptor isoform

A; FDC, follicular dendritic cells; G, granulocytes; GC, germinal center; GITR, glucocorticoid-induced TNFR-related protein; GPI, glycosyl phosphatidylinositol; HTA, human

thymocyte antigen; HVEM, herpesvirus entry mediator; ICOS, inducible T-cell co-stimulator; Ig, immunoglobulin; IgG, immunoglobulin G; LAG-3, lymphocyte-activation gene

3; LCA, leukocyte common antigen; LPS, lipopolysaccharide; MHC-I, major histocompatibility complex class I; MP, macrophages; Mr, relative molecular mass; NK, natural

killer cells; P, platelets; PBT, peripheral blood T cells; PD-1, programmed cell death-1; PI, phosphatidylinositol; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C;

PTP, protein tyrosine phosphatase; PVR, polio virus receptor; PVRL2, polio virus receptor-related 2; RCA, regulators of complement activation; SABP, seminal actin binding

protein; TCR, T-cell receptor; Tfh, T follicular helper cells; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TNF, tumor necrosis factor; TNFR, tumor necrosis factor

receptor.

Note: For an expanded list of cluster of differentiation (CD) human antigens, see Harrison’s Online at http://www.accessmedicine.com; and for a full list of CD human

antigens from the most recent Human Workshop on Leukocyte Differentiation Antigens (VII), D Mason, P Andre, A Bensussan, et al (eds): Leucocyte Typing VII. Oxford:

Oxford University Press, 2002.

Source: Compiled from T Kishimoto et al (eds): Leukocyte Typing VI. New York: Garland Publishing, 1997; R Brines et al: Immunol Today 18S:1, 1997; and D Mason et al: CD

antigens 2002. Blood 99:3877, 2002.

nonhematopoietic cell types leads to activation/production of the

complement cascade, cytokines, and antimicrobial peptides as effector molecules. In addition, pathogen PAMPs as host danger signal

molecules activate DCs to mature and to express molecules on the

DC surface that optimize antigen presentation to respond to foreign

antigens.

■ PATTERN RECOGNITION

Major PRR families of proteins include transmembrane proteins, such

as the Toll-like receptors (TLRs) and C-type lectin receptors (CLRs),

and cytoplasmic proteins, such as the retinoic acid–inducible gene

(RIG)-1-like receptors (RLRs) and NOD-like receptors (NLRs) (Table

349-3). A major group of PRR collagenous glycoproteins with C-type

lectin domains are termed collectins and include the serum protein

mannose-binding lectin (MBL). MBL and other collectins, as well as

two other protein families—the pentraxins (such as C-reactive protein

and serum amyloid P) and macrophage scavenger receptors—all have

the property of opsonizing (coating) bacteria for phagocytosis by macrophages and can also activate the complement cascade to lyse bacteria.

Integrins are cell-surface adhesion molecules that affect attachment

between cells and the extracellular matrix and mediate signal transduction that reflects the chemical composition of the cell environment. For

example, integrins signal after cells bind bacterial lipopolysaccharide

(LPS) and activate phagocytic cells to ingest pathogens.

There are multiple connections between the innate and adaptive

immune systems; these include (1) a plasma protein, LPS-binding

protein, that binds and transfers LPS to the macrophage LPS receptor, CD14; (2) a human family of proteins called Toll-like receptor

proteins (TLRs), some of which are associated with CD14, bind LPS,

and signal epithelial cells, DCs, and macrophages to produce cytokines and upregulate cell-surface molecules that signal the initiation

of adaptive immune responses (Fig. 349-1, Table 349-3; and (3)

families of intracellular microbial sensors called NLRs and RLRs. Proteins in the Toll family can be expressed on macrophages, DCs, and

(Continued)

Introduction to the Immune System

2675CHAPTER 349

TABLE 349-3 Pattern Recognition Receptors (PRRs) and Their Ligands

PRRs LOCALIZATION LIGAND ORIGIN OF THE LIGAND

TLR

TLR1 Plasma membrane Triacyl lipoprotein Bacteria

TLR2 Plasma membrane Lipoprotein Bacteria, viruses, parasite, self

TLR3 Endolysosome dsRNA Virus

TLR4 Plasma membrane LPS Bacteria, viruses, self

TLR5 Plasma membrane Flagellin Bacteria

TLR6 Plasma membrane Diacyl lipoprotein Bacteria, viruses

TLR7 (human TLR8) Endolysosome ssRNA Virus, bacteria, self

TLR9 Endolysosome CpG-DNA Virus, bacteria, protozoa, self

TLR10 Endolysosome Unknown Unknown

TLR11 Plasma membrane Profilin-like molecule Protozoa

RLR

RIG-I Cytoplasm Short dsRNA, triphosphate dsRNA RNA viruses, DNA virus

MDA5 Cytoplasm Long dsRNA RNA viruses (Picornaviridae)

LGP2 Cytoplasm Unknown RNA viruses

NLR

NOD1 Cytoplasm iE-DAP Bacteria

NOD2 Cytoplasm MDP Bacteria

CLR

Dectin-1 Plasma membrane β2

-Glucan Fungi

Dectin-2 Plasma membrane β2

-Glucan Fungi

MINCLE Plasma membrane SAP130 Self, fungi

Abbreviations: CLR, C-type lectin receptors; dsRNA, double-strand RNA; iE-DAP, D-glutamyl-meso-diaminopimelic acid moiety; LGP2, Laboratory of Genetics and Physiology

2 protein encoded by the gene DHX58; MDA5, melanoma differentiation-associated protein 5; MDP, MurNAc-L-Ala-D-isoGln, also known as muramyl dipeptide; MINCLE,

macrophage-inducible C-type lectin; NLR, NOD-like receptor; NOD, NOTCH protein domain; RIG, retinoic acid–inducible gene; RLR, RIG-like receptors; SAP130, Sin-3

associated protein 130; TLR, Toll-like receptor.

Source: Reproduced with permission from O Takeuchi: Pattern recognition receptors and inflammation. Cell 140:805, 2010.

CD14

LPS

Inflammatory

cytokines and/

Nucleus or chemokines

TLR9

CpG

ssRNA

TLR7 Endosome

or TLR8

MYD88

TRIF MYD88 TIRAP MYD88

TRIF

TRAM

Triacylated

lipopeptides

Diacylated

lipopeptides Flagellin Unknown

TLR4 TLR2

TLR1

TLR2

TLR6

TLR5 TLR10

Flagellin

TLR 11

Plasma membrane

TRAF-6

IRAK

MAPK NF-κB

NF-κB

IFN-β

IRF3

IRF3

TLR3

dsRNA

Endosome

FIGURE 349-1 Overview of major TLR signaling pathways. All TLRs signal through MYD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also

engage TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein). TLR3 signals through TRIF (Toll-interleukin 1 receptor domain-containing adapter-inducing

interferon-β). TRIF is also used in conjunction with TRAM (TRIF-related adaptor molecule) in the TLR4-MYD88-independent pathway. Dashed arrows indicate translocation

into the nucleus. dsRNA, double-strand RNA; IFN, interferon; IRF3, interferon regulatory factor 3; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; NF-κB,

nuclear factor-κB; ssRNA, single-strand RNA; TLR, Toll-like receptor. (Reproduced with permission from D Van Duin et al: Triggering TLR signaling in vaccination. Trends

Immunol 27:49, 2006.)

2676 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

B cells as well as on a variety of non-hematopoietic cell types, including

respiratory epithelial cells. Eleven TLRs have been identified in humans

(Table 349-3). Upon ligation, TLRs activate a series of intracellular

events that lead to the killing of bacteria- and viral-infected cells as well

as to the recruitment and ultimate activation of antigen-specific T and

B lymphocytes (Fig. 349-1). Importantly, signaling by massive amounts

of LPS through TLR4 leads to the release of high levels of cytokines

that mediate LPS-induced shock. Mutations in TLR4 proteins in mice

protect from LPS shock, and TLR mutations in humans protect from

LPS-induced inflammatory diseases such as LPS-induced asthma.

Two other families of cytoplasmic PRRs are the NLRs and the RLRs.

These families, unlike the TLRs, are composed primarily of soluble

intracellular proteins that scan host cell cytoplasm for intracellular

pathogens (Tables 349-2 and 349-3).

The intracellular microbial sensors, NLRs, after triggering, form

large cytoplasmic complexes termed inflammasomes, which are aggregates of molecules including NOD-like receptor pyrin (NLRP) proteins (Table 349-4). Inflammasomes activate inflammatory caspases

and IL-1β in the presence of nonbacterial danger signals (cell stress)

and bacterial PAMPs. Mutations in inflammasome proteins can lead

to chronic inflammation in a group of periodic febrile diseases called

autoinflammatory syndromes. Polymorphisms in inflammasome components can either protect or enhance risk of infections or autoimmune/

autoinflammatory diseases (Table 349-4). Inflammasomes are activated

upon sensing of PAMPs. Crystallopathies are diseases caused by tissue

crystal deposition such as monosodium urate that can activate the

inflammasome and, in the case of urate deposition, can lead to gout with

arthritis or renal disease.

■ EFFECTOR CELLS OF INNATE IMMUNITY

Cells of the innate immune system and their roles in the first line

of host defense are listed in Table 349-5. Equally important as their

roles in the mediation of innate immune responses are the roles that

each cell type plays in recruiting T and B lymphocytes of the adaptive

immune system to engage in specific pathogen responses.

Monocytes-Macrophages Monocytes arise from precursor cells

within bone marrow (Fig. 349-2) and circulate with a half-life ranging from 1 to 3 days. Monocytes leave the peripheral circulation via

capillaries and migration into a vast extravascular cellular pool. Tissue

macrophages arise from monocytes that have migrated out of the circulation and by in situ proliferation of macrophage precursors in tissue.

Common locations where tissue macrophages (and certain of their

specialized forms) are found are lymph node, spleen, bone marrow,

perivascular connective tissue, serous cavities such as the peritoneum,

pleura, skin connective tissue, lung (alveolar macrophages), liver

(Kupffer cells), bone (osteoclasts), central nervous system (microglia

cells), and synovium (type A lining cells).

In general, monocytes-macrophages are on the first line of defense

associated with innate immunity and ingest and destroy microorganisms through the release of toxic products such as hydrogen peroxide

(H2

O2

) and nitric oxide (NO). Inflammatory mediators produced by

macrophages attract additional effector cells such as neutrophils to

the site of infection. Macrophage mediators include prostaglandins;

leukotrienes; platelet activating factor; cytokines such as IL-1, TNF-α,

IL-6, and IL-12; and chemokines (Tables 349-6 and 349-7).

Although monocytes-macrophages were originally thought to be

the major APCs of the immune system, it is now clear that cell types

called dendritic cells are the most potent and effective APCs in the body

(see below). Monocytes-macrophages mediate innate immune effector

functions such as destruction of antibody-coated bacteria, tumor cells,

or even normal hematopoietic cells in certain types of autoimmune

cytopenias. Monocytes-macrophages ingest bacteria or are infected

by viruses, and in doing so, they frequently undergo programmed cell

death or apoptosis. Macrophages that are infected by intracellular infectious agents are recognized by DCs as infected and apoptotic cells and

are phagocytosed by DCs. In this manner, DCs “cross-present” infectious agent antigens of macrophages to T cells. Activated macrophages

can also mediate antigen-nonspecific lytic activity and eliminate cell

types such as tumor cells in the absence of antibody. This activity

is largely mediated by cytokines (i.e., TNF-α and IL-1). Monocytesmacrophages express lineage-specific molecules (e.g., the cell-surface

LPS receptor, CD14) as well as surface receptors for a number of molecules, including the Fc region of IgG, activated complement components, and various cytokines (Table 349-6).

Dendritic Cells Human DCs contain several subsets, including

myeloid DCs and plasmacytoid DCs. Myeloid DCs can differentiate

into either macrophages-monocytes or tissue-specific DCs. In contrast

to myeloid DCs, plasmacytoid DCs are inefficient APCs but are potent

producers of type I IFN (e.g., IFN-α) in response to viral infections.

The maturation of DCs is regulated through cell-to-cell contact and

soluble factors, and DCs attract immune effectors through secretion of

chemokines. When DCs come in contact with bacterial products, viral

proteins, or host proteins released as danger signals from distressed

host cells (Fig. 349-2), infectious agent molecules bind to various

TLRs and activate DCs to release cytokines and chemokines that drive

cells of the innate immune system to become activated to respond to

invading organisms, and recruit T and B cells of the adaptive immune

system to respond. Plasmacytoid DCs produce antiviral IFN-α that

activates NK cell killing of pathogen-infected cells; IFN-α also activates

T cells to mature into antipathogen cytotoxic (killer) T cells. Following

contact with pathogens, both plasmacytoid and myeloid DCs produce

chemokines that attract helper and cytotoxic T cells, B cells, polymorphonuclear cells, and naïve and memory T cells as well as regulatory

T cells to ultimately dampen the immune response once the pathogen

is controlled. TLR engagement on DCs upregulates MHC class II, B7-1

(CD80), and B7-2 (CD86), which enhance DC-specific antigen presentation and induce cytokine production. Thus, DCs are important

bridges between early (innate) and later (adaptive) immunity. DCs also

modulate and determine the types of immune responses induced by

pathogens via the TLRs expressed on DCs (TLR7–9 on plasmacytoid

DCs, TLR4 on monocytoid DCs) and via the TLR adapter proteins

that are induced to associate with TLRs (Fig. 349-1, Table 349-1). In

addition, other PRRs, such as C-type lectins, NLRs, and mannose

receptors, upon ligation by pathogen products, activate cells of the

adaptive immune system and, like TLR stimulation, by a variety of factors, determine the type and quality of the adaptive immune response

that is triggered.

Innate Lymphoid Cells ILCs are comprised of ILC1, ILC2, ILC3,

lymphoid tissue inducer (LTi), and NK cells. ILC1, ILC2, ILC3, and

LTi are primarily tissue resident cells. ILCs develop from a common

lymphoid precursor in the bone marrow and then differentiate into

one of five ILC types—ILC1, ILC2, ILC3, LTi, or NK cells—based on

their development (Fig. 349-3A) and function (Fig. 349-3B). NK cells

and ILC1s depend on T-bet transcription factor for their development

and function and produce IFN-γ. NK cells are innate analogues to CD8

cytotoxic T cells in that they both mediate granzyme and perforinbased cytotoxic cell activity. ILC1s mirror CD4 TH1 lymphocytes and

react to intracellular pathogens such as viruses and to tumors. ILC2s

are the analogues of TH2 CD4 T cells and are dependent on GATA3 and

RORα factors and produce type 2 cytokines, such as IL-5 and IL-13.

ILC2s respond to extracellular parasites and allergens. ILC3s and LTi

cells are dependent on transcription factor RORγ1 and produce IL-17.

ILC3s are analogues of CD4 TH17 lymphocytes and attack extracellular pathogens such as bacteria and fungi. LTi cells are critical for

the formation of lymph nodes and Peyer’s patches in gut during fetal

development (Fig. 349-3B).

NK cells express surface receptors for the Fc portion of IgG (FcR)

(CD16) and for NCAM-I (CD56), and many NK cells express T

lineage markers, particularly CD2, CD7, and CD8, and proliferate

in response to IL-2. NK cells arise in both bone marrow and thymic

microenvironments. In addition to mediating cytotoxicity to foreign

or malignant cells, NK cells also mediate ADCC. ADCC is the binding

of an opsonized (antibody-coated) target cell to an Fc receptor-bearing

effector cell via the Fc region of antibody, resulting in target cell lysis.

NK cell cytotoxicity is the MHC-unrestricted, non-antibody-mediated