Introduction to the Immune System

2695CHAPTER 349

helper (Tfh) cells. T cell–B cell interactions that lead to high-affinity

antibody production require (1) processing of native antigen by B cells

and expression of peptide fragments on the B-cell surface for presentation to TH cells, (2) the ligation of B cells by both the TCR complex

and the CD40 ligand, (3) induction of the process termed antibody

isotype switching in antigen-specific B-cell clones, and (4) induction of

the process of affinity maturation of antibody in the germinal centers

of B-cell follicles of lymph node and spleen.

Naïve B cells express cell-surface IgD and IgM, and initial contact

of naïve B cells with antigen is via binding of native antigen to B-cell

surface IgM. T-cell cytokines, released following TH2 cell contact with

B cells or by a “bystander” effect, induce changes in Ig gene conformation that promote recombination of Ig genes. These events then result

in the switching of expression of heavy chain exons in a triggered B

cell, leading to the secretion of IgG, IgA, or, in some cases, IgE antibody

with the same V region antigen specificity as the original IgM antibody,

for response to a wide variety of extracellular bacteria, protozoa, and

helminths. CD40 ligand expression by activated T cells is critical for

induction of B-cell antibody isotype switching and for B-cell responsiveness to cytokines. Patients with mutations in T-cell CD40 ligand

have B cells that are unable to undergo isotype switching, resulting

in lack of memory B-cell generation and the immunodeficiency syndrome of X-linked hyper-IgM syndrome (Chaps. 350 and 351).

■ IMMUNE TOLERANCE AND AUTOIMMUNITY

Immune tolerance is defined as the absence of activation of pathogenic

autoreactivity to self-antigens. Autoimmune diseases are syndromes

caused by the activation of T or B cells or both, with no evidence of

other causes such as infections or malignancies (Chaps. 350 and 355).

Immune tolerance and autoimmunity are present normally in health;

when abnormal, they represent extremes from the normal state. For

example, low levels of autoreactivity of T and B cells with self-antigens

in the periphery are critical to T- and B-cell survival. Similarly, low

levels of autoreactivity and thymocyte recognition of self-antigens

in the thymus are the mechanisms whereby normal T cells are positively selected to survive and leave the thymus to respond to foreign

microbes in the periphery and T cells highly reactive to self-antigens

are negatively selected and die to prevent overly self-reactive T cells

from migrating to the periphery (central tolerance). However, not

all self-antigens are expressed in the thymus to delete highly selfreactive T cells, and there are mechanisms for induction of tolerance

in peripheral T cells as well. Unlike the presentation of microbial antigens by mature DCs, the presentation of self-antigens by immature

DCs neither activates nor matures the DCs to express high levels of

co-stimulatory molecules such as B7-1 (CD80) or B7-2 (CD86). When

peripheral T cells are stimulated by DCs expressing self-antigens in the

context of HLA molecules, sufficient stimulation of T cells occurs to

keep them alive, but otherwise, they remain anergic, or nonresponsive,

until T cells contact a DC with high levels of co-stimulatory molecules

expressing microbial antigens and become activated to respond to the

microbe. If B cells have high self-reactive BCRs, they normally undergo

either deletion in the bone marrow or receptor editing to express a

less autoreactive receptor. Although many autoimmune diseases are

characterized by abnormal or pathogenic autoantibody production

(Table 349-10), most autoimmune diseases are caused by a combination of excess T- and B-cell reactivity.

Multiple factors contribute to the genesis of autoimmune disease syndromes, including genetic susceptibility (e.g. HLAB27 with ankylosing

spondylitis), environmental immune stimulants such as drugs (e.g., procainamide and phenytoin [Dilantin] with drug-induced systemic lupus

erythematosus), infectious agent triggers (such as Epstein-Barr virus and

autoantibody production againstred blood cells and platelets), and loss of T

regulatory cells (leading to thyroiditis, adrenalitis, and oophoritis).

Immunity at Mucosal Surfaces Mucosa covering the respiratory,

digestive, and urogenital tracts; the eye conjunctiva; the inner ear; and

the ducts of all exocrine glands contain cells of the innate and adaptive

mucosal immune system that protect these surfaces against pathogens.

In the healthy adult, mucosa-associated lymphoid tissue (MALT)

contains 80% of all immune cells within the body and constitutes the

largest mammalian lymphoid organ system.

MALT has three main functions: (1) to protect the mucous membranes from invasive pathogens; (2) to prevent uptake of foreign antigens from food, commensal organisms, and airborne pathogens and

particulate matter; and (3) to prevent pathologic immune responses

from foreign antigens if they do cross the mucosal barriers of the body.

MALT is a compartmentalized system of immune cells that functions

independently from systemic immune organs. Whereas the systemic

immune organs are essentially sterile under normal conditions and

respond vigorously to pathogens, MALT immune cells are continuously

bathed in foreign proteins and commensal bacteria, and they must

select those pathogenic antigens that must be eliminated. MALT contains anatomically defined foci of immune cells in the intestine, tonsil,

appendix, and peribronchial areas that are inductive sites for mucosal

immune responses. From these sites, immune T and B cells migrate

to effector sites in mucosal parenchyma and exocrine glands where

mucosal immune cells eliminate pathogen-infected cells. In addition to

mucosal immune responses, all mucosal sites have strong mechanical

and chemical barriers and cleansing functions to repel pathogens.

Key components of MALT include specialized epithelial cells called

“membrane” or “M” cells that take up antigens and deliver them to

DCs or other APCs. Effector cells in MALT include B cells producing

antipathogen neutralizing antibodies of secretory IgA as well as IgG

isotype, T cells producing similar cytokines as in systemic immune

system response, and T helper and cytotoxic T cells that respond to

pathogen-infected cells.

Secretory IgA is produced in amounts of >50 mg/kg of body weight

per 24 h and functions to inhibit bacterial adhesion, inhibit macromolecule absorption in the gut, neutralize viruses, and enhance antigen

elimination in tissue through binding to IgA and receptor-mediated

transport of immune complexes through epithelial cells.

Recent studies have demonstrated the importance of commensal gut

and other mucosal bacteria to the health of the human immune system.

Normal commensal flora induces anti-inflammatory events in the gut

and protects epithelial cells from pathogens through TLRs and other

PRR signaling. When the gut is depleted of normal commensal flora,

the immune system becomes abnormal, with loss of TH1 T-cell function. Restoration of the normal gut flora can reestablish the balance in

T helper cell ratios characteristic of the normal immune system. Diet

also has an impact on the gut microbiome. Altered microbiome composition has been etiologically related to obesity, insulin resistance, and

diabetes. When the gut barrier is intact, either antigens do not transverse the gut epithelium or, when pathogens are present, a self-limited,

protective MALT immune response eliminatesthe pathogen (Fig. 349-8).

However, when the gut barrier breaks down, immune responses to

commensal flora antigens can cause inflammatory bowel diseases such

as Crohn’s disease and, perhaps, ulcerative colitis (Chap. 326). Uncontrolled MALT immune responses to food antigens, such as gluten, can

cause celiac disease (Chap. 326).

■ THE CELLULAR AND MOLECULAR CONTROL OF

PROGRAMMED CELL DEATH

The process of apoptosis (programmed cell death) plays a crucial role

in regulating normal immune responses to antigen. In general, a wide

variety of stimuli trigger one of several apoptotic pathways to eliminate

microbe-infected cells, eliminate cells with damaged DNA, or eliminate activated immune cells that are no longer needed (Fig. 349-9).

The largest known family of “death receptors” is the TNF receptor

(TNF-R) family (TNF-R1, TNF-R2, Fas [CD95], death receptor 3

[DR3], death receptor 4 [DR4; TNF-related apoptosis-including ligand

receptor 1, or TRAIL-R1], and death receptor 5 [DR5, TRAIL-R2]);

their ligands are all in the TNF-α family. Binding of ligands to these

death receptors leads to a signaling cascade that involves activation

of the caspase family of molecules that leads to DNA cleavage and cell

death. Two other pathways of programmed cell death involve nuclear

p53 in the elimination of cells with abnormal DNA and mitochondrial

cytochrome c to induce cell death in damaged cells (Fig. 349-9). A number of human diseases have now been described that result from, or are

2696 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

AUTOANTIGEN AUTOIMMUNE DISEASES

Aminoacyl-tRNA synthetase

(several)

Polymyositis, dermatomyositis

Cardiolipin Systemic lupus erythematosus,

antiphospholipid syndrome

Carbonic anhydrase II Systemic lupus erythematosus, Sjögren’s

syndrome, systemic sclerosis

Collagen (multiple types) Rheumatoid arthritis, systemic lupus

erythematosus, progressive systemic

sclerosis

Centromere-associated proteins Systemic sclerosis

DNA-dependent nucleosidestimulated ATPase

Dermatomyositis

Fibrillarin Scleroderma

Fibronectin Systemic lupus erythematosus,

rheumatoid arthritis, morphea

Glucose-6-phosphate isomerase Rheumatoid arthritis

β2-Glycoprotein I (B2-GPI) Primary antiphospholipid syndrome

Golgin (95, 97, 160, 180) Heat shock

protein

Sjögren’s syndrome, systemic lupus

erythematosus, rheumatoid arthritis,

various immune-related disorders

Hemidesmosomal protein 180 Bullous pemphigoid, herpes gestationis,

cicatricial pemphigoid

Histone H2A-H2B-DNA Systemic lupus erythematosus

IgE receptor Chronic idiopathic urticaria

Keratin Rheumatoid arthritis

Ku-DNA-protein kinase Systemic lupus erythematosus

Ku-nucleoprotein La

phosphoprotein (La 55-B)

Connective tissue syndrome Sjögren’s

syndrome

Myeloperoxidase Necrotizing and crescentic

glomerulonephritis, systemic vasculitis

Proteinase 3 (PR3) Granulomatosis with polyangiitis

(Wegener’s), Churg-Strauss syndrome

RNA polymerase I–III (RNP) Systemic sclerosis, systemic lupus

erythematosus

Signal recognition protein (SRP54) Polymyositis

Topoisomerase-1 (Scl-70) Scleroderma, Raynaud’s syndrome

Tublin Chronic liver disease, visceral

leishmaniasis

Vimentin Systemic autoimmune disease

Plasma Protein and Cytokine Autoimmunity

C1 inhibitor Autoimmune C1 deficiency

C1q Systemic lupus erythematosus, membrane

proliferative glomerulonephritis

Cytokines (IL-1α, IL-1β, IL-6, TNF-α,

IFN-γ IL17A, IL-17F, GM-CSF)

IL-1α, IL-1β: rheumatoid arthritis,

systemic sclerosis, systemic lupus

erythematosus; IL-6: bacterial infections;

IFN-γ: bacterial infections, varicella-zoster

virus reactivation; IL-17A, IL-17F: chronic

mucocutaneous candidiasis; GM-CSF:

pulmonary alveolar proteinosis, fungal

infections

Factor II, factor V, factor VII, factor

VIII, factor IX, factor X, factor XI,

thrombin vWF

Prolonged coagulation time

Glycoprotein IIb/IIIg and Ib/IX Autoimmune thrombocytopenia purpura

IgA Immunodeficiency associated with

systemic lupus erythematosus, pernicious

anemia, thyroiditis, Sjögren’s syndrome,

and chronic active hepatitis

Oxidized LDL (OxLDL) Atherosclerosis

Cancer and Paraneoplastic Autoimmunity

Amphiphysin Neuropathy, small-cell lung cancer

Cyclin B1 Hepatocellular carcinoma

AUTOANTIGEN AUTOIMMUNE DISEASES

Cell- or Organ-Specific Autoimmunity

Acetylcholine receptor Myasthenia gravis

Actin Chronic active hepatitis, primary biliary

cirrhosis

Adenine nucleotide translator (ANT) Dilated cardiomyopathy, myocarditis

β-Adrenoreceptor Dilated cardiomyopathy

Aromatic l-amino acid

decarboxylase

Autoimmune polyendocrine syndrome

type 1 (APS-1)

Asialoglycoprotein receptor Autoimmune hepatitis

Bactericidal/permeabilityincreasing protein (Bpi)

Cystic fibrosis vasculitides

Calcium-sensing receptor Acquired hypoparathyroidism

Cholesterol side-chain cleavage

enzyme (CYP11a)

Autoimmune polyglandular syndrome-1

Collagen type IV-α3-chain Goodpasture’s syndrome

Cytochrome P450 2D6 (CYP2D6) Autoimmune hepatitis

Desmin Crohn’s disease, coronary artery disease

Desmoglein 1 Pemphigus foliaceus

Desmoglein 3 Pemphigus vulgaris

F-actin Autoimmune hepatitis

GM gangliosides Guillain-Barré syndrome

Glutamate decarboxylase (GAD65) Type 1 diabetes, stiff-person syndrome

Glutamate receptor (GLUR) Rasmussen encephalitis

H/K ATPase Autoimmune gastritis

17-α-Hydroxylase (CYP17) Autoimmune polyglandular syndrome-1

21-Hydroxylase (CYP21) Addison’s disease

IA-2 (ICA512) Type 1 diabetes

Insulin Type 1 diabetes, insulin hypoglycemic

syndrome (Hirata’s disease)

Insulin receptor Type B insulin resistance, acanthosis,

systemic lupus erythematosus

Intrinsic factor type 1 Pernicious anemia

Leukocyte function-associated

antigen (LFA-1)

Treatment-resistant Lyme arthritis

Myelin-associated glycoprotein

(MAG)

Polyneuropathy

Myelin-basic protein Multiple sclerosis, demyelinating diseases

Myelin oligodendrocyte

glycoprotein (MOG)

Multiple sclerosis

Myosin Rheumatic fever

p-80-Collin Atopic dermatitis

Pyruvate dehydrogenase

complex-E2 (PDC-E2)

Primary biliary cirrhosis

Sodium iodide symporter (NIS) Graves’ disease, autoimmune

hypothyroidism

SOX-10 Vitiligo

Thyroid and eye muscle shared

protein

Thyroid-associated ophthalmopathy

Thyroglobulin Autoimmune thyroiditis

Thyroid peroxidase Autoimmune Hashimoto’s thyroiditis

Thyrotropin receptor Graves’ disease

Tissue transglutaminase Celiac disease

Transcription coactivator p75 Atopic dermatitis

Tryptophan hydroxylase Autoimmune polyglandular syndrome-1

Tyrosinase Vitiligo, metastatic melanoma

Tyrosine hydroxylase Autoimmune polyglandular syndrome-1

Systemic Autoimmunity

ACTH ACTH deficiency

Aminoacyl-tRNA histidyl synthetase Myositis, dermatomyositis

TABLE 349-10 Recombinant or Purified Autoantigens Recognized by Autoantibodies Associated with Human Autoimmune Disorders

(Continued)

Introduction to the Immune System

2697CHAPTER 349

AUTOANTIGEN AUTOIMMUNE DISEASES

Cancer and Paraneoplastic Autoimmunity (continued)

DNA topoisomerase II Liver cancer

Desmoplakin Paraneoplastic pemphigus

Gephyrin Paraneoplastic stiff-person syndrome

Hu proteins Paraneoplastic encephalomyelitis

Neuronal nicotinic acetylcholine

receptor

Subacute autonomic neuropathy, cancer

p53 Cancer, systemic lupus erythematosus

AUTOANTIGEN AUTOIMMUNE DISEASES

p62 (IGF-II mRNA-binding protein) Hepatocellular carcinoma (China)

Recoverin Cancer-associated retinopathy

Ri protein Paraneoplastic opsoclonus myoclonus

ataxia

βIV spectrin Lower motor neuron syndrome

Synaptotagmin Lambert-Eaton myasthenic syndrome

Voltage-gated calcium channels Lambert-Eaton myasthenic syndrome

Yo protein Paraneoplastic cerebellar degeneration

Source: From A Lernmark et al: J Clin Invest 108:1091, 2001; Ceppelano G et al: Am J Clin Exp Immunol 1:136, 2012; C-L Ku et al: Hum Genet 139:783, 2020.

TABLE 349-10 Recombinant or Purified Autoantigens Recognized by Autoantibodies Associated with Human Autoimmune Disorders (Continued)

Death ligand

Death Receptor

Death-receptor-mediated Mitochondrial-mediated

(FAS, TNF, TRAIL) (γ Radiation)

Oxygen radicals DNA injury

BIM, PUMA, other

BH3-only proteins

BCL-XL-BCL2 BCL2-BCL-XL

?

BAX

FADD

Capsase 8

BAK

c-FLIP

SMAC/DIABLO

SMAC/DIABLO Caspase 3

Caspase 9 activation

Substrate cleavage

Apoptosis

IAPS

IAPS

BID

APAF1

Cytochrome c

Cytochrome c

tBID

FIGURE 349-9 Pathways of cellular apoptosis. There are two major pathways of apoptosis: the death-receptor pathway, which is mediated by activation of death receptors,

and the BCL2-regulated mitochondrial pathway, which is mediated by noxious stimuli that ultimately lead to mitochondrial injury. Ligation of death receptors recruits the

adaptor protein FAS-associated death domain (FADD). FADD in turn recruits caspase 8, which ultimately activates caspase 3, the key “executioner” caspase. Cellular

FLICE-inhibitory protein (c-FLIP) can either inhibit or potentiate binding of FADD and caspase 8, depending on its concentration. In the intrinsic pathway, proapoptotic BH3

proteins are activated by noxious stimuli, which interact with and inhibit antiapoptotic BCL2 or BCL-XL. Thus, BAX and BAK are free to induce mitochondrial permeabilization

with release of cytochrome c, which ultimately results in the activation of caspase 9 through the apoptosome. Caspase 9 then activates caspase 3. SMAC/DIABLO is also

released after mitochondrial permeabilization and acts to block the action of inhibitors of apoptosis protein (IAPs), which inhibit caspase activation. There is potential

cross-talk between the two pathways, which is mediated by the truncated form of BID (tBID) that is produced by caspase 8–mediated BID cleavage; tBID acts to inhibit

the BCL2-BCL-XL pathway and to activate BAX and BAK. There is debate (indicated by the question mark) as to whether proapoptotic BH3 molecules (e.g., BIM and

PUMA) act directly on BAX and BAK to induce mitochondrial permeability or whether they act only on BCL2-BCL-XL. APAF1, apoptotic protease-activating factor 1; BH3,

BCL homologue; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand. (From RS Hotchkiss et al: Cell death in disease: mechanisms and emerging

therapeutic concepts. N Engl J Med 361:1570, 2009. Copyright © (2009) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

associated with, mutated apoptosis genes. These include mutations in

the Fas and Fas ligand genes in autoimmune and lymphoproliferation

syndromes, and multiple associations of mutations in genes in the

apoptotic pathway with malignant syndromes (Chap. 350).

■ MECHANISMS OF IMMUNE-MEDIATED DAMAGE

TO MICROBES OR HOST TISSUES

Several responses by the host innate and adaptive immune systems

to foreign microbes culminate in rapid and efficient elimination of

microbes. In these scenarios, the classic weapons of the adaptive

immune system (T cells, B cells) interface with cells (macrophages,

DCs, NK cells, neutrophils, eosinophils, basophils) and soluble products (microbial peptides, pentraxins, complement and coagulation

systems) of the innate immune system (Chaps. 64 and 352).

There are five general phases of host defenses: (1) migration of

leukocytes to sites of antigen localization; (2) antigen-nonspecific

recognition of pathogens by macrophages and other cells and systems of the innate immune system; (3) specific recognition of foreign

2698 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

1. Tethering

and rolling

2. Chemokine

signal

3. Arrest 4. Polarization and

diapedesis

5. Junctional

rearrangement

6. Proteolysis

8. DC migration

to draining LN

7. Interstitial

migration

Cytokinestimulated

parenchymal

cell

ECM with GAG

Collagen

CCL19

CCL21 CCR7

ICAM-1

or

VCAM-1

Inflammatory

chemoattractants Selectin sialomucin

Resting actve

integrins

GPCR

Damaged

or inflamed

tissue

Basement

membrane

Lymph vessel

DC

Blood vessel lumen

FIGURE 349-10 Key migration steps of immune cells at sites of inflammation. Inflammation due to tissue damage or infection induces the release of cytokines (not shown)

and inflammatory chemoattractants (red arrowheads) from distressed stromal cells and “professional” sentinels, such as mast cells and macrophages (not shown). The

inflammatory signals induce upregulation of endothelial selectins and immunoglobulin “superfamily” members, particularly ICAM-1 and/or VCAM-1. Chemoattractants,

particularly chemokines, are produced by or translocated across venular endothelial cells (red arrow) and are displayed in the lumen to rolling leukocytes. Those leukocytes

that express the appropriate set of trafficking molecules undergo a multistep adhesion cascade (steps 1–3) and then polarize and move by diapedesis across the venular

wall (steps 4 and 5). Diapedesis involves transient disassembly of endothelial junctions and penetration through the underlying basement membrane (step 6). Once in the

extravascular (interstitial) space, the migrating cell uses different integrins to gain “footholds” on collagen fibers and other ECM molecules, such as laminin and fibronectin,

and on inflammation-induced ICAM-1 on the surface of parenchymal cells (step 7). The migrating cell receives guidance cues from distinct sets of chemoattractants,

particularly chemokines, which may be immobilized on glycosaminoglycans (GAG) that “decorate” many ECM molecules and stromal cells. Inflammatory signals also

induce tissue dendritic cells (DCs) to undergo maturation. Once DCs process material from damaged tissues and invading pathogens, they upregulate CCR7, which allows

them to enter draining lymph vessels that express the CCR7 ligand CCL21 (and CCL19). In lymph nodes (LNs), these antigen-loaded mature DCs activate naïve T cells and

expand pools of effector lymphocytes, which enter the blood and migrate back to the site of inflammation. T cells in tissue also use this CCR7-dependent route to migrate

from peripheral sites to draining lymph nodes through afferent lymphatics. (Reproduced with permission from AD Luster et al: Immune cell migration in inflammation: present

and future therapeutic targets. Nat Immunol 6:1182, 2005.)

antigens mediated by T and B lymphocytes; (4) amplification of the

inflammatory response with recruitment of specific and nonspecific

effector cells by complement components, cytokines, kinins, arachidonic acid metabolites, and mast cell–basophil products; and (5) macrophage, neutrophil, and lymphocyte participation in destruction of

antigen with ultimate removal of antigen particles by phagocytosis

(by macrophages or neutrophils) or by direct cytotoxic mechanisms

(involving macrophages, neutrophils, DCs, and lymphocytes). Under

normal circumstances, orderly progression of host defenses through

these phases results in a well-controlled immune and inflammatory

response that protects the host from the offending antigen. However,

dysfunction of any of the host defense systems can damage host tissue

and produce clinical disease. Furthermore, for certain pathogens or

antigens, the normal immune response itself might contribute substantially to the tissue damage. For example, the immune and inflammatory

response in the brain to certain pathogens such as M. tuberculosis may

be responsible for much of the morbidity rate of this disease in that

organ system (Chap. 178). In addition, the morbidity rate associated

with certain pneumonias such as that caused by Pneumocystis jiroveci

may be associated more with inflammatory infiltrates than with the

tissue-destructive effects of the microorganism itself (Chap. 220).

Molecular Basis of Lymphocyte–Endothelial Cell Interac- tions The control of lymphocyte circulatory patterns between the

bloodstream and peripheral lymphoid organs operates at the level

of lymphocyte–endothelial cell interactions to control the specificity of lymphocyte subset entry into organs. Similarly, lymphocyte–

endothelial cell interactions regulate the entry of lymphocytes into

inflamed tissue. Adhesion molecule expression on lymphocytes and

endothelial cells regulates the retention and subsequent egress of

lymphocytes within tissue sites of antigenic stimulation, delaying

cell exit from tissue and preventing reentry into the circulating

lymphocyte pool (Fig. 349-10). All types of lymphocyte migration

begin with lymphocyte attachment to specialized regions of vessels,

termed high endothelial venules (HEVs). An important concept is

that adhesion molecules do not generally bind their ligand until a

conformational change (ligand activation) occurs in the adhesion

molecule that allows ligand binding. Induction of a conformationdependent determinant on an adhesion molecule can be accomplished

by cytokines or via ligation of other adhesion molecules on the cell.

The first stage of lymphocyte–endothelial cell interactions, attachment and rolling, occurs when lymphocytes leave the stream of flowing

blood cells in a postcapillary venule and roll along venule endothelial

Introduction to the Immune System

2699CHAPTER 349

cells (Fig. 349-10). Lymphocyte rolling is mediated by the l-selectin

molecule (LECAM-1, LAM-1, CD62L) and slows cell transit time

through venules, allowing time for activation of adherent cells.

The second stage of lymphocyte–endothelial cell interactions, firm

adhesion with activation-dependent stable arrest, requires stimulation of

lymphocytes by chemoattractants or by endothelial cell–derived cytokines. Cytokines thought to participate in adherent cell activation include

members of the IL-8 family, platelet-activation factor, leukotriene B4

,

and C5a. In addition, HEVs express chemokines, SLC (CCL21) and

ELC (CCL19), which participate in this process. Following activation by

chemoattractants, lymphocytes shed l-selectin from the cell surface and

upregulate cell CD11b/18 (MAC-1) or CD11a/18 (LFA-1) molecules,

resulting in firm attachment of lymphocytes to HEVs.

Lymphocyte homing to peripheral lymph nodes involves adhesion of

l-selectin to glycoprotein HEV ligands collectively referred to as peripheral node addressin (PNAd), whereas homing of lymphocytes to intestine

Peyer’s patches primarily involves adhesion of the a4β7 integrin to

mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on the Peyer’s

patch HEVs. However, for migration to mucosal Peyer’s patch lymphoid

aggregates, naïve lymphocytes primarily use l-selectin, whereas memory lymphocytes use α4β7 integrin. α4β1 integrin (CD49d/CD29,

VLA-4)–VCAM-1 interactions are important in the initial interaction

of memory lymphocytes with HEVs of multiple organs in sites of

inflammation (Table 349-11).

The third stage of leukocyte emigration in HEVs is sticking and

arrest. Sticking of the lymphocyte to endothelial cells and arrest at the

site of sticking are mediated predominantly by ligation of a1β2 integrin

LFA-1 to the integrin ligand ICAM-1 on HEVs. Whereas the first three

stages of lymphocyte attachment to HEVs take only a few seconds,

the fourth stage of lymphocyte emigration, transendothelial migration,

takes ~10 min. Although the molecular mechanisms that control

lymphocyte transendothelial migration are not fully characterized, the

HEV CD44 molecule and molecules of the HEV glycocalyx (extracellular matrix) are thought to play important regulatory roles in this

process (Fig. 349-10). Finally, expression of matrix metalloproteases

capable of digesting the subendothelial basement membrane, rich in

nonfibrillar collagen, appears to be required for the penetration of

lymphoid cells into the extravascular sites.

Abnormal induction of HEV formation and use of the molecules discussed above have been implicated in the induction and maintenance of

inflammation in a number of chronic inflammatory diseases. In animal

models of type 1 diabetes mellitus, MAdCAM-1 and GlyCAM-1 have

been shown to be highly expressed on HEVs in inflamed pancreatic

islets, and treatment of these animals with inhibitors of l-selectin and

a4 integrin function blocked the development of type 1 diabetes mellitus (Chap. 403). A similar role for abnormal induction of the adhesion

molecules of lymphocyte emigration has been suggested in rheumatoid

arthritis (Chap. 358), Hashimoto’s thyroiditis (Chap. 382), Graves’

disease (Chap. 382), multiple sclerosis (Chap. 444), Crohn’s disease

(Chap. 326), and ulcerative colitis (Chap. 326).

Immune-Complex Formation Clearance of antigen by

immune-complex formation between antigen, complement, and antibody is a highly effective mechanism of host defense. However,

depending on the level of immune complexes formed and their physicochemical properties, immune complexes may or may not result in

host and foreign cell damage. After antigen exposure, certain types of

soluble antigen-antibody complexes freely circulate and, if not cleared

TABLE 349-11 Trafficking Molecules Involved in Inflammatory Disease Processes

PROPOSED LEUKOCYTE RECEPTORS FOR ENDOTHELIAL TRAFFIC SIGNALS

DISEASE KEY EFFECTOR CELL l-SELECTIN, LIGAND G PROTEIN-COUPLED RECEPTOR INTEGRINa

Acute Inflammation

Myocardial infarction Neutrophil PSGL-1 CXCR1, CXCR2, PAFR, BLT1 LFA-1, Mac-1

Stroke Neutrophil l-Selectin, PSGL-1 CXCR1, CXCR2, PAFR, BLT1 LFA-1, Mac-1

Ischemia-reperfusion Neutrophil PSGL-1 CXCR1, CXCR2, PAFR, BLT1 LFA-1, Mac-1

TH1 Inflammation

Atherosclerosis Monocyte PSGL-1 CCR1, CCR2, BLT1, CXCR2, CX3CR1 VLA-4

TH1 PSGL-1 CXCR3, CCR5 VLA-4

Multiple sclerosis TH1 PSGL-1 (?) CXCR3, CXCR6 VLA-4, LFA-1

Monocyte PSGL-1 (?) CCR2, CCR1 VLA-4, LFA-1

Rheumatoid arthritis Monocyte PSGL-1 CCR1, CCR2 VLA-1, VLA-2, VLA-4, LFA-1

TH1 PSGL-1 CXCR3, CXCR6 VLA-1, VLA-2, VLA-4, LFA-1

Neutrophil l-Selectin, PSGL-1 CXCR2, BLT1 LFA-1b

Psoriasis Skin-homing TH1 CLA CCR4, CCR10, CXCR3 VLA-4c

, LFA-1

Crohn’s disease Gut-homing TH1 PSGL-1 CCR9, CXCR3 α4, β7, LFA-1

Type 1 diabetes TH1 PSGL-1 (?) CCR4, CCR5 VLA-4, LFA-1

CD8 l-Selectin (?), PSGL-1 (?) CXCR3 VLA-4, LFA-1

Allograft rejection CD8 PSGL-1 CXCR3, CX3CR1, BLT1 VLA-4, LFA-1

B cell l-Selectin, PSGL-1 CXCR5, CXCR4 VLA-4, LFA-1

Hepatitis CD8 PSGL-1 CXCR3, CCR5, CXCR6 VLA-4

Lupus TH1 None CXCR6 VLA-4d

Plasmacytoid DC l-Selectin, CLA CCR7, CXCR3, ChemR23 LFA-1, Mac-1

B cell CLA (?) CXCR5, CXCR4 LFA-1

TH2 Inflammation

Asthma TH2 PSGL-1 CCR4, CCR8, BLT1 LFA-1

Eosinophil PSGL-1 CCR3, PAFR, BLT1 VLA-4, LFA-1

Mast cells PSGL-1 CCR2, CCR3, BLT1 VLA-4, LFA-1

Atopic dermatitis Skin-homing TH2 CLA CCR4, CCR10 VLA-4, LFA-1

a

Various β1

 integrins have been linked in different ways in basal lamina and interstitial migration of distinct cell types and inflammatory settings. b

In some settings, Mac-1

has been linked to transmigration. c

CD44 can act in concert with VLA-4 in particular models of leukocyte arrest. d

TH2 cells require VAP-1 to traffic to inflamed liver.

Source: Reproduced with permission from AD Luster et al: Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182, 2005.

2700 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

by the reticuloendothelial system, can be deposited in blood vessel

walls and in other tissues such as renal glomeruli and cause vasculitis

or glomerulonephritis syndromes (Chaps. 314 and 363). Deficiencies

of early complement components are associated with inefficient clearance of immune complexes and immune complex–mediated tissue

damage in autoimmune syndromes, whereas deficiencies of the later

complement components are associated with susceptibility to recurrent

Neisseria infections (Table 349-12).

Immediate-Type Hypersensitivity Helper T cells that drive

antiallergen IgE responses are usually TH2-type inducer T cells that

secrete IL-4, IL-5, IL-6, and IL-10. A subset of Tfh, Tfh13, cells have

been identified that produce IL-4, IL-5, and IL-13, which play a key role

in responses to allergens that induce IgE and mediate anaphylaxis. Mast

cells and basophils have high-affinity receptors for the Fc portion of

IgE (FcRI), and cell-bound antiallergen IgE effectively “arms” basophils

and mast cells. Mediator release is triggered by antigen (allergen)

interaction with Fc receptor-bound IgE, and the mediators released

are responsible for the pathophysiologic changes of allergic diseases.

Mediators released from mast cells and basophils can be divided into

three broad functional types: (1) those that increase vascular permeability and contract smooth muscle (histamine, platelet-activating

factor, SRS-A, BK-A), (2) those that are chemotactic for or activate

other inflammatory cells (ECF-A, NCF, leukotriene B4

), and (3) those

that modulate the release of other mediators (BK-A, platelet-activating

factor) (Chap. 352).

Cytotoxic Reactions of Antibody In this type of immunologic

injury, complement-fixing (C1-binding) antibodies against normal or

foreign cells or tissues (IgM, IgG1, IgG2, IgG3) bind complement via

the classic pathway and initiate a sequence of events similar to that

initiated by immune-complex deposition, resulting in cell lysis or tissue

injury. Examples of antibody-mediated cytotoxic reactions include red

cell lysis in transfusion reactions, Goodpasture’s syndrome with anti–

glomerular basement membrane antibody formation, and pemphigus

vulgaris with anti-epidermal antibodies inducing blistering skin disease.

Delayed-Type Hypersensitivity Reactions Inflammatory

reactions initiated by mononuclear leukocytes and not by antibody

alone have been termed delayed-type hypersensitivity reactions. The

term delayed has been used to contrast a secondary cellular response

that appears 48–72 h after antigen exposure with an immediate hypersensitivity response generally seen within 12 h of antigen challenge

and initiated by basophil mediator release or preformed antibody.

For example, in an individual previously infected with M. tuberculosis organisms, intradermal placement of tuberculin purified protein

derivative as a skin test challenge results in an indurated area of skin at

48–72 h, indicating previous exposure to tuberculosis.

The cellular events that result in classic delayed-type hypersensitivity responses are centered on T cells (predominantly, although

not exclusively, IFN-γ, IL-2, and TNF-α-secreting TH1-type helper

T cells) and macrophages. Recently, NK cells have been suggested to

play a major role in the form of delayed hypersensitivity that occurs

following skin contact with immunogens. First, local immune and

inflammatory responses at the site of foreign antigen upregulate endothelial cell adhesion molecule expression, promoting the accumulation

of lymphocytes at the tissue site. In the scheme outlined in Fig. 349-2,

antigen is processed by DCs and presented to small numbers of CD4+

T cells expressing a TCR specific for the antigen. IL-12 produced by

APCs induces T cells to produce IFN-γ (TH1 response). Macrophages

frequently undergo epithelioid cell transformation and fuse to form

multinucleated giant cells in response to IFN-γ. This type of mononuclear cell infiltrate is termed granulomatous inflammation. Examples of

diseases in which delayed-type hypersensitivity plays a major role are

fungal infections (histoplasmosis; Chap. 212), mycobacterial infections

(tuberculosis, leprosy; Chaps. 178 and 179), chlamydial infections

(lymphogranuloma venereum; Chap. 189), helminth infections (schistosomiasis; Chap. 234), reactions to toxins (berylliosis; Chap. 289), and

hypersensitivity reactions to organic dusts (hypersensitivity pneumonitis; Chap. 288). In addition, delayed-type hypersensitivity responses

play important roles in tissue damage in autoimmune diseases such

as rheumatoid arthritis, temporal arteritis, and granulomatosis with

polyangiitis (GPA) (Chaps. 358 and 363).

Autophagy Autophagy is a process that involves a 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 M. tuberculosis, in part by initiation of phagosome maturation and enhancing

MHC class II antigen presentation to CD4 T cells.

■ CLINICAL EVALUATION OF IMMUNE FUNCTION

Clinical assessment of immunity requires investigation of the four

major components of the immune system that participate in host

defense and in the pathogenesis of autoimmune diseases: (1) humoral

immunity (B cells); (2) cell-mediated immunity (T cells, monocytes);

(3) phagocytic cells of the reticuloendothelial system (macrophages), as

well as polymorphonuclear leukocytes; and (4) complement. Clinical

problems that require an evaluation of immunity include chronic infections, recurrent infections, unusual infecting agents, and certain autoimmune syndromes. The type of clinical syndrome under evaluation

can provide information regarding possible immune defects (Chap.

351). Defects in cellular immunity generally result in viral, mycobacterial, and fungal infections. An extreme example of deficiency in cellular

immunity is AIDS (Chap. 197). Antibody deficiencies result in recurrent bacterial infections, frequently with organisms such as S. pneumoniae and Haemophilus influenzae (Chap. 351). Disorders of phagocyte

function are frequently manifested by recurrent skin infections, often

due to Staphylococcus aureus (Chap. 64). Finally, deficiencies of early

and late complement components are associated with autoimmune

phenomena and recurrent Neisseria infections (Table 349-12). For further discussion of useful initial screening tests of immune function,

see Chap. 351.

■ IMMUNOTHERAPY

Many therapies for autoimmune and inflammatory diseases involve the

use of nonspecific immune-modulating or immunosuppressive agents

such as glucocorticoids or cytotoxic drugs. The goal of development

of new treatments for immune-mediated diseases is to design ways to

specifically interrupt pathologic immune responses, leaving nonpathologic immune responses intact (Chap. 350). Novel ways to interrupt

pathologic immune responses that are under investigation include the

use of anti-inflammatory cytokines or specific cytokine inhibitors as

TABLE 349-12 Complement Deficiencies and Associated Diseases

COMPONENT ASSOCIATED DISEASES

Classic Pathway

Clq, Clr, Cls, C4 Immune-complex syndromes,a

 pyogenic infections

C2 Immune-complex syndromes,a

 few with pyogenic

infections

C1 inhibitor Rare immune-complex disease, few with pyogenic

infections

C3 and Alternative Pathway C3

C3 Immune-complex syndromes,a

 pyogenic infections

D Pyogenic infections

Properdin Neisseria infections

I Pyogenic infections

H Hemolytic-uremic syndrome

Membrane Attack Complex

C5, C6, C7, C8 Recurrent Neisseria infections, immune-complex disease

C9 Rare Neisseria infections

a

Immune-complex syndromes include systemic lupus erythematosus (SLE) and SLElike syndromes, glomerulonephritis, and vasculitis syndromes.

Source: After JA Schifferli, DK Peters: Lancet 322:957, 1983. Copyright 1983.

Mechanisms of Regulation and Dysregulation of the Immune System

2701CHAPTER 350

anti-inflammatory agents, the use of monoclonal antibodies against T

or B lymphocytes as therapeutic agents, the use of intravenous Ig for

certain infections and immune complex–mediated diseases, the use of

specific cytokines to reconstitute components of the immune system,

and bone marrow transplantation to replace the pathogenic immune

system with a more normal immune system (Chaps. 64, 202, 350, and

351). CTLA-4 inhibitors such as ipilimumab and tremelimumab and

anti-PD-1 antibodies such as nivolumab have been shown to reverse

CD8 T-cell exhaustion in melanoma and other solid tumors and induce

immune cell control of tumor growth (Chap. 350). A new technique

that engineers autologous T cells to express antibody receptors that

target leukemic cells, termed chimeric antigen receptor T cells (CAR T

cells), has been approved by the U.S. Food and Drug Administration

(FDA) for the treatment of certain types of leukemias and lymphomas

(Chap. 350).

Cell-based therapies have been studied for many years, including ex

vivo activation of NK cells for reinfusion into patients with malignancies, and DC therapy of ex vivo priming of DCs for enhanced presentation of cancer antigens, with reinfusion of primed DCs into the patient.

One such strategy for DC therapy has been approved by the FDA for

treatment of advanced prostate cancer.

Cytokines and Cytokine Inhibitors Several TNF inhibitors are

used as biological therapies in the treatment of rheumatoid arthritis; these include monoclonal antibodies, TNF-R Fc fusion proteins,

and Fab fragments. Use of anti-TNF-α antibody therapies such as

adalimumab, infliximab, and golimumab has resulted in clinical

improvement in patients with these diseases and has opened the way

for targeting TNF-α to treat other severe forms of autoimmune and/or

inflammatory disease (Chap. 350). Blockage of TNF-α has been effective in rheumatoid arthritis, psoriasis, Crohn’s disease, and ankylosing

spondylitis. Other cytokine inhibitors are recombinant soluble TNF-α

receptor (R) fused to human Ig and anakinra (soluble IL-1 receptor

antagonist, or IL-1ra). The treatment of autoinflammatory syndromes

(Table 349-5) with recombinant IL-1 receptor antagonist can prevent

symptoms in these syndromes, because the overproduction of IL-1β is

a hallmark of these diseases.

TNF-αR-Fc fusion protein (etanercept) and IL-1ra act to inhibit the

activity of pathogenic cytokines in rheumatoid arthritis, i.e., TNF-α

and IL-1, respectively. Similarly, anti-IL-6, IFN-β, and IL-11 act

to inhibit pathogenic proinflammatory cytokines. Anti-IL-6 (tocilizumab) inhibits IL-6 activity, whereas IFN-β and IL-11 decrease IL-1

and TNF-α production (Chap. 350). Of particular note has been the

successful use of IFN-γ in the treatment of the phagocytic cell defect in

chronic granulomatous disease (Chap. 64).

TH17 CD4 T cells have been implicated in the pathogenesis of psoriasis, ulcerative colitis, and other autoimmune diseases. Monoclonal

antibodies have now been developed that target cytokines (IL-12,

IL-23) that induce TH17 T-cell differentiation and are licensed by the

FDA for treatment of psoriasis. Monoclonal antibodies that directly

target IL-17 have also recently been licensed for psoriasis and psoriatic arthritis treatment. Monoclonal antibodies against cytokines and

immunoregulatory molecules are now mainstays of cancer and autoimmune disease therapy (Chap. 350).

Intravenous Immunoglobulin (IVIg) IVIg has been used successfully to block reticuloendothelial cell function and immune

complex clearance in various immune cytopenias such as immune

thrombocytopenia (Chap. 115). In addition, IVIg is useful for prevention of tissue damage in certain inflammatory syndromes such

as Kawasaki disease (Chap. 363) and as Ig replacement therapy for

certain types of immunoglobulin deficiencies (Chap. 351). In addition,

controlled clinical trials support the use of IVIg in selected patients

with graft-versus-host disease, multiple sclerosis, myasthenia gravis,

Guillain-Barré syndrome, and chronic demyelinating polyneuropathy.

Stem Cell Transplantation Hematopoietic stem cell transplantation (SCT) is now being comprehensively studied to treat several

autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, and scleroderma. The goal of immune reconstitution in

autoimmune disease syndromes is to replace a dysfunctional immune

system with a normally reactive immune cell repertoire. Preliminary

results in patients with scleroderma and lupus have showed encouraging results. Controlled clinical trials in these three diseases are now

being launched in the United States and Europe to compare the toxicity

and efficacy of conventional immunosuppression therapy with that of

myeloablative autologous SCT. Recently, SCT was used in the setting of

HIV-1 infection. HIV-1 infection of CD4+ T cells requires the presence

of surface CD4 receptor and the chemokine receptor 5 (CCR5) coreceptor. Studies have demonstrated that patients who are homozygous

for a 32-bp deletion in the CCR5 allele do not express CD4+ T-cell

CCR5 and thus are resistant to HIV-1 infection with HIV-1 strains

that use this co-receptor. Stem cells from a homozygous CCR5 delta32

donor were transplanted to an HIV-1-infected patient following standard conditioning for such transplants, and the patient has maintained

long-term control of the virus without antiretrovirals. Thus, a number

of recent insights into immune system function have spawned a new

field of interventional immunotherapy and have enhanced the prospect

for development of more specific and nontoxic therapies for immune

and inflammatory diseases (Chap. 350).

■ FURTHER READING

Altan-Bonnet G, Mukherjee R: Cytokine-mediated communication: A quantitative appraisal of immune complexity. Nat Rev Immunol 19:205, 2020.

Dupage M, Bluestone JA: Harnessing the plasticity of CD4+T cells

to treat immune-mediated disease. Nat Rev Immunol 3:149, 2016.

McLean KC, Mandal M: It takes three receptors to raise a B cell.

Trends Immunol 41:629, 2020.

Mulay SR, Anders HJ: Crystallopathies. N Engl J Med 374:25, 2016.

Netea MG et al: Defining trained immunity and its role in health and

disease. Nat Rev Immunol 20:375, 2020.

Pellicci DG et al: Thymic development of unconventional T cells:

How NKT, cells MAIT cells and γδ T cells emerge. Nat Rev Immunol

20:756, 2020.

Pulendran B: Immunology taught by vaccines. Science 366:1074,

2019.

Ratner D et al: Bacterial secretion systems and regulation of inflammasome activation. J Leuk Bio 101:165, 2017.

Vivier E et al: Innate lymphoid cells: 10 years on. Cell 174:1054, 2018.

Yang F et al: The diverse biological functions of neutrophils, beyond

the defense against infections. Inflammation 40:311, 2017.

DEFINITIONS

Anergy—A reversible tolerance mechanism in which the T or B cell is

in an unresponsive state following an antigen encounter but remains

alive.

Chimeric antigen receptor T cells (CAR T)—Synthetic hybrid receptors

created by recombinant techniques that combine an extracellular

domain, usually derived from an antibody single-chain variable

fragment (scFv), with intracellular signaling domains from activating co-stimulatory molecules (from endogenous T-cell receptors

350 Mechanisms of Regulation

and Dysregulation of the

Immune System

Barton F. Haynes, Kelly A. Soderberg,

Anthony S. Fauci

2702 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

[TCRs], CD28, or 4-1BB) that allow for retargeting of T cells to

antigens on malignant cells.

Checkpoint inhibition therapy—A form of cancer immunotherapy

whereby antibodies against T-cell or antigen-presenting cell regulators of immune cell inhibition are used to activate cytotoxic T cells

to kill tumor cells.

Co-stimulation of T cells—A secondary signal that T cells require for

activation following presentation of peptide antigen by major histocompatibility complex (MHC) molecules to TCRs on either CD4 or

CD8 T cells. A prime mediator of co-stimulation is the T cell CD28

molecule binding to B7-1 (CD80, CD86) on antigen-presenting

cells.

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 and pathologic inflammatory

and immune responses.

Immune homeostasis—Balanced protective immunity that does not

overreact to pathogens and harm the host, and immunity that is not

deficient and does not predispose the host to harmful infections or

malignancies.

Immunoediting—Process of immunity selecting clones of cancer cells

with reduced immunogenicities resulting in tumor escape.

Natural killer cells—Lymphocytes with cytotoxic potential for host

cells with non-self-antigens, such as cells infected with pathogens or

tumor cells expressing tumor-specific neoantigens.

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.

T regulatory cells (Tregs)—CD4 and CD8 T cells regulated by the transcription factor FOXP3 that play roles in downmodulating B- and

T-cell responses in peripheral lymphoid tissues to prevent deleterious immune activation that can lead to autoimmune diseases.

Tumor-infiltrating lymphocytes—Lymphocytes that infiltrate tumors

that may be in the exhausted state and upon which checkpoint inhibition therapy works.

Tumor neoantigens—Molecules in malignant cells that develop mutations that create non-self-antigens that are recognized by host T cells

as non-self and against which tumor-infiltrating CD4 and CD8 T

cells respond to reject the tumor.

INTRODUCTION

Immune homeostasis is the maintenance of a balance between immunity that protects the host and dysregulated immunity that predisposes

the host to harmful infections, autoimmunity, or malignancies. Overactivity of innate and adaptive immunity leads to autoimmunity and/

or inflammatory diseases. Underactivity of immune responses can lead

to both immune deficiency and autoimmunity. Disruption of immune

homeostasis contributes either directly or indirectly to many forms of

disease. Thus, a major goal of immunotherapy is to either maintain

immune homeostasis or reestablish immune balance in diseases of

immune dysregulation.

This is an important time in the study of the biology of the immune

system. The development of high-throughput genome sequencing, full

genome transcriptome analysis, proteomics, metabolomics, and the

realization of the importance of the human microbiome to immune

system homeostasis have provided remarkable opportunities for development of new treatments for immune-mediated and malignant

diseases. The emerging concept is that the immune system itself can

be manipulated to be used as a therapeutic intervention for cancer

and also can be safely manipulated for control of autoimmune disease. Moreover, new data are emerging that immune dysregulation is

involved in the pathogenesis of diseases not traditionally thought of as

immune-related, such as neurodegenerative diseases and atherosclerotic cardiovascular disease, and that the normal process of aging is

associated with inflammatory processes.

Thus, a new frontier of medicine is to understand basic regulatory

mechanisms of the innate and adaptive immune system with the goal

of learning specific rules of immune system regulation, such that

eventually the immune system can be “tuned” to safely stay in the

zone of immune homeostasis and, at the same time, effectively protect against emerging and reemerging infectious diseases or eliminate

malignancies as they arise. Moreover, when inflammatory or autoimmune diseases arise, effective strategies of immune regulation can be

developed to safely treat them.

Thus, this chapter builds on Chap. 349, Introduction to the

Immune System, to discuss T- and B-cell immunoregulation, to

highlight recent successes in translating basic immunologic research

into treatments of various hematopoietic and solid tumors, and to

discuss mechanisms of immune dysregulation in autoimmunity and

aging.

MECHANISMS OF REGULATION OF T-CELL

ACTIVATION

Key roles of T cells are to respond to and eliminate cells bearing foreign

antigens and to ignore cells expressing self-antigens. To respond to foreign antigens, stimulating cells must deliver an activating co-stimulating

signal in addition to TCR ligation. To avoid responding to cells bearing

self-antigens, T cells must also maintain immune tolerance. Central

T-cell tolerance is maintained by autoreactive T-cell deletion in the

thymus, while peripheral tolerance is maintained by regulatory T

cells (Treg), T-cell anergy, and peripheral clonal deletion (see section

below, Mechanisms of Immune Dysregulation in Autoimmune Disease). Thus, T-cell activation is an integral component of the adaptive

immune response to pathogens as well as to tumor neoantigens.

Two stimulatory signals are required for T-cell activation. One T-cell

signal is delivered by antigen peptide presented in the context of MHC

(Chap. 349). However, in the absence of a co-stimulating signal, the T

cell will not be activated by peptide MHC alone but rather will become

anergic or unresponsive. A second co-stimulatory signal is needed

for T-cell activation, resulting in cytoskeletal remodeling, production

of cytokines, and cell survival and differentiation. In addition to the

TCR/CD3 complex (Chap. 349), T cells express a complex array of

co-stimulatory as well as inhibitory molecules that bind to their respective receptors on the surface of antigen-presenting cells (APCs) and

orchestrate both initiation and control of T-cell activation to maintain

immune homeostasis (Fig. 350-1, and see Chap. 349, Table 349-1).

Of these, CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), and

programmed cell death protein 1 (PD-1) and their ligands were among

the first to be recognized to be central to control of T-cell activation.

The CD28 molecule is a member of the immunoglobulin (Ig) superfamily and is the original member of a subfamily of co-stimulatory or

inhibitory molecules on the surface of T cells that includes CTLA-4,

inducible T-cell costimulator (ICOS), PD-1, T-cell immunoreceptor

with Ig and ITIM domains (TIGIT), and B- and T-cell attenuator

(BTLA) (Fig. 350-1). CD28 stimulates intracellular signaling through

AKT and PI3 kinase, resulting in induction of NF-κB, AP-1, and

NFAT, which are all critical for T-cell activation and differentiation

(Chap. 349, Fig. 349-7). CTLA-4 and PD-1 are CD28 subfamily members that control T-cell activation by inhibiting the stimulating activity

of CD28 and other T-cell co-stimulatory molecules.

CTLA-4 is a key negative regulator of T-cell activation that downmodulates the T-cell response to antigen by interaction with its ligands,

B7-1 and B7-2, to control unchecked T-cell proliferation. CTLA-4

is upregulated following TCR engagement with MHC/peptide, thus

dampening TCR signaling by competing with CD28 binding to B7

ligands (B7-1 [CD80] and B7-2 [CD86]) on APCs by virtue of higher

affinity of CTLA-4 for B7 ligands. In this manner, T cells respond to

foreign antigen but are prevented from damaging host tissues due to

overexuberant responses (Fig. 350-2A). CTLA-4 thus mediates its

dampening effect on T-cell activation by competing with T-cell CD28

binding to B7 receptors, as well as through the suppressive effect of

CTLA-4+ Tregs. The human CTLA4 gene is just one of several genes

in which monogenetic mutations are associated with decreased Treg

function and autoimmune syndromes (Table 350-1).

PD-1 is also a major inhibitory molecule of T-cell activation by

interaction with its ligands PD-L1 and PD-L2 on APCs (Fig. 350-1).

Mechanisms of Regulation and Dysregulation of the Immune System

2703CHAPTER 350

CHECKPOINT INHIBITION

THERAPY FOR CANCER

The field of immune checkpoint therapy has joined surgery, radiation, chemotherapy, and targeted therapy as a

mainstay for cancer therapy. There are now an extensive

number of therapeutic monoclonal antibodies approved

by the U.S. Food and DrugAdministration (FDA), initially

starting with melanoma in 2011–2014 and now available

for a wide range of malignancies including kidney, lung,

liver, head and neck, and gastric tumors (Table 350-2).

Both CTLA-4 and PD-1 blockade have proved remarkably

successful in treating a number of tumors, but only in

a fraction of patients. Because each receptor ligand pair

regulates distinct T-cell inhibitory pathways, combination

therapy using anti-PD-1 and anti-CTLA-4 antibodies has

been especially useful and has induced significant tumor

regression in ~50% of melanoma patients. What is different in the use of checkpoint inhibitor antibodies is that the

therapy is not targeted to the tumor per se, but rather is

targeted to immunoregulatory molecules on host T cells.

Moreover, therapy is not targeted to specific molecules

on tumors, but rather is targeted to release exhausted

tumor-infiltrating T cells (TILs) to be activated to kill

tumor cells by removing immune regulatory inhibition.

CTLA-4 induces tumor rejection by a number of

mechanisms. First, anti-CTLA-4 antibody mediates

direct blockade of CTLA-4 competition with CD28 for

B7-1 and B7-2 co-stimulatory ligands, thus allowing

CD28-mediated T-cell activation (Fig. 350-2B). Tumor

cells do not express B7 molecules; thus, CTLA-4 blockade likely occurs

in tumor-draining lymph nodes where exhausted T cells interact with

APCs presenting tumor neoantigens to T cells. A second mechanism of

CTLA-4 blockade–induced tumor rejection is depletion or reduction

in suppressive effects of Tregs. Suppressive effect of Tregs include secretion of immunosuppressive cytokines such as transforming growth

factor (TGF)-β or interleukin (IL) 10 or by direct inhibition of T-cell

proliferation and/or cytolytic activity. A third potential mechanism of

anti-CTLA-4 blockade is remodeling and broadening of the peripheral

TCR repertoire for tumor antigens. Evidence suggests that the effects

of anti-CTLA-4 antibody are restricted primarily to tumor neoantigenspecific CD8 T cells within the tumor microenvironment and not to

T cells in lymph nodes or spleen.

PD-1 blockade by PD-1 antibody also induces tumor regression

by reversing T-cell exhaustion, leading to enhanced T-cell killing

While initially thought to be a cell death receptor, PD-1 is rapidly

expressed upon activation of T and B cells and is also a marker of T

follicular helper CD4+ T cells in B-cell germinal centers. PD-1 acts

to dampen T-cell activation by dephosphorylation of CD28 via the

Src homology region 2-containing protein tyrosine phosphatase 2

(SHP2).

Although a marker of immune cell activation, PD-1 is also a marker

for exhausted T cells. T-cell exhaustion is an important mechanism of

maintaining immune homeostasis and preventing host tissue T-cell

damage, but also leads to immune dysfunction in the setting of chronic

antigenic stimulation such as occurs in chronic viral diseases (HIV-1,

hepatitis C) and in cancer. Chronic viral diseases and tumors lead to

transcriptional and metabolic signatures that define the exhausted

T-cell state. T-cell exhaustion has been a major roadblock to overcome

for successful cancer immunotherapy.

T cell APC, tumor, or other cells

CTLA4 (CD152)

CD28

TCR

PD1 (CD279)

ICOS (CD278)

OX40 (CD134)

GITR (CD357)

CD40

4-IBB (CD137)

TIM-3

BTLA-4 (CD272)

TIGIT

DNAM-1(CD226)

LAG-3 (CD223)

B7-2 (CD86)

B7-1 (CD80)

MHC Class I or II

PD-LI (CD274)

PD-L2 (CD273)

ICOS-L (CD275)

OX40L (CD252)

GITRL

CD40L (CD154)

4-IBBL (CD137L)

HVEM

CD155

CD112

MHC Class II

Phosphatidylserine

Galectin-9

FIGURE 350-1 Regulatory stimulating or inhibiting molecules on T cells or antigen-presenting cells

(APCs), tumor cells, or other cells.

APC

CTLA4

T cell

PI3K and AKT

signaling Ca2+ and MAPK signaling

Cell intrinsic signaling?

Competitive

inhibition

Other signaling?

Tumor cell

APC APC

pMHC

TCR

A B

Activation Attenuation Therapy

APC

PD-1 PD-1

B7-1

B7-2 B7-1

B7-2 B7-1

B7-2

PD-1 anti-PD-L1

Enhanced

effector

activity

Enhanced

effector

activity

antiPD-L1

antiCTLA4

Tumor cell Tumor cell

SHP2

PD-1

PD-L1

PD-L2

B7-1

P7-2

CD28 TCR

pMHC

PD-L1 PD-L1

CTLA4

CTLA4 CD28 CD28

FIGURE 350-2 Molecular mechanisms of CTLA-4 and PD-1 attenuation of T-cell activation and schematic of the molecular mechanisms of action of CTLA-4 and PD-1

blockade. A. Schematic of the molecular interactions and downstream signaling induced by ligation of CTLA-4 and PD-1 by their respective ligands. The possibility of

additional downstream cell-intrinsic signaling mechanisms is highlighted for both CTLA-4 and PD-1. B. The stepwise progression of T-cell activation, attenuation by normal

regulatory mechanisms, and release of such negative regulation by therapeutic intervention using anti-CTLA-4 or anti-PD-1 antibodies is outlined. (Reprinted from SC Wei

et al: Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069, 2018, with permission from AACR.)

2704 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 350-1 Monogenetic Mutations That Lead to Immune Dysregulation and Autoimmunity

MUTATIONS AND FUNCTIONAL DEFICITS DISEASES OR SYNDROME

RAG1, RAG2; lymphopenia with recombinase deficiency Severe combined immune deficiency (Omenn’s syndrome) with autoreactive T cells

Fas, FasL, CASP10; apoptosis defects Autoimmune lymphoproliferative disease

AIRE, deletion chromosome 22q11.2; decrease in central

tolerance

Ch. 22q11.2: DiGeorge’s syndrome with autoimmune T cells

AIRE: autoimmunity, polyneuropathy, candidiasis, ectodermal dysplasia (APECED syndrome)

FOXP3, CD25, CTLA-4, LRBA; decrease in peripheral immune

tolerance with decrease in Treg function

FOXP3: IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)

CD25: enteropathy, dermatitis, autoimmunity, susceptibility to infections

CTLA-4: associated with multiple autoimmune syndromes

LRBA: infant with enteritis; hypogammaglobulinemia, autoimmune cytopenias

STAT-1, STAT-3; modulation of type 1 interferons STAT-1 deficiency: decreased IFN-γ, susceptible to TB

STAT-1 gain of function: chronic mucocutaneous candidiasis with autoimmune diseases

STAT-3 deficiency: hyper-IgE syndrome (Job’s syndrome)

STAT-3 gain of function: lymphopenia, autoimmune cytopenias, diabetes, enteropathy

C1q, C1r/s, C2, C4; complement deficiencies Systemic lupus erythematosus (SLE)

FcfRII, FcfRIII, C-reactive protein, complement receptor for

C3bi (ITGAM or compliment receptor 3), COPA, tripeptidyl

peptidase; lack of removal of cell debris

FcfII, FcfIII, CRP, complement receptor for C3bi: systemic lupus erythematosus

COPA: autoimmune lung, renal, joint disease

Tripeptidyl peptidase II: susceptibility to bacterial, viral, and fungal pathogens

Phosphoinositide-3-kinase delta (PI3Kc), phospho-lipase

Cf2, protein kinase Cc (PKCc) deficiency, protein kinase Cc

(PKCc) deficiency; hyperactivation of lymphocytes

PI3Kc: lymphoproliferation, respiratory infections, hypogammaglobulinemia

Phospholipase Cf2: cold urticaria, antibody deficiency, autoimmunity

PKCc: early-onset SLE with decreased B-cell apoptosis, autoantibody-mediated renal disease and

lymphoproliferation

Activation-induced cytidine deaminase (AID); classimpaired B-cell development

Hyper IgM syndrome type 2, low IgA, IgG, recurrent bacterial switch recombination; infections,

autoimmune cytopenias, SLE

Abbreviations: APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AIRE, autoimmune regulator; COPA, gene encodes the non-clathrin-coated

vesicular coat protein, COP-alpha; CTLA-4, cytotoxic T lymphocyte associated protein-4; FcγR, Fcγ receptor; FOXP3, forkhead box P3; IFN, interferon; ITGAM, integrin alpha

M; LRBA, lipopolysaccharide (LPS)-responsive and beige-like anchor protein; RAG, recombinase activating gene; STAT, signal transducer and activator of transcription; TB,

tuberculosis; Treg, T regulatory cell.

Source: B Grimbacher et al: The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol 137:3,

2016.

of tumor cells. Optimal PD-1 antibody-mediated checkpoint inhibition is seen when infiltrating CD8 T cells are present in the tumor

microenvironment and reversal of the exhausted T-cell state can

occur in situ. PD-1 blockade can also act by reversal of metabolic

reprogramming of exhausted T cells, leading to enhanced cytolytic

T-cell effector function. Antibodies to the primary PD-1 receptor,

PD-L1, are also sufficient to induce reversal of T-cell exhaustion and

induce tumor killing and are approved by the FDA for treatment of

non-small-cell lung cancer (Table 350-2). PD-L1 is induced on tumor

cells by TH1 cytokines, which may explain anti-PD-L1 efficacy since TH1

cytokines drive cytotoxic T-cell responses (Chap. 349). Efficacy of

anti-PD-L1 may also be due in part to mediation of antibody-dependent

cellular cytotoxicity (ADCC) killing of tumor cells (Chap. 349).

Tumor cells express neoantigens that are targets for T-cell recognition

in the tumor microenvironment. Immune pressure within the tumor

microenvironment can select for tumor cells that present few or mutated

neoantigens and thus escape ongoing antitumor immunity. Moreover,

a low number of tumor-infiltrating lymphocytes, tumor microenvironment production of immunosuppressive indoleamine 2,3-dioxygenase

(IDO), and tumor infiltration with either myeloid-derived suppressor

cells or Tregs can also limit checkpoint blockade therapy.

Other strategies for improving the immunoregulation of antitumor

responses include combinations of anti-PD-1, anti-CTLA-4, or antiPD-L1 antibodies with other checkpoint inhibitors (see Chap. 349,

Table 349-1, and Fig. 350-1). For example, engagement of the ICOS

pathway enhances the efficacy of CTLA-4 blockade in animal models

of cancer immunotherapy. T-cell immunoglobulin and mucin-domain

containing-3 (TIM-3), TIGIT, or lymphocyte-activation gene 3 (LAG-3)

inhibition has been suggested to enhance checkpoint inhibition and

augment CD8 tumor cell killing. A new transcription factor, thymocyteselection-associated high mobility box (TOX), has been defined as a

key controller of CD8 T-cell exhaustion. Thus, TOX inhibition could

synergize with checkpoint inhibition therapy to reverse the T-cell

exhaustion state. Finally, the combination of checkpoint inhibition

with other cancer treatments including chemotherapy, radiation, tumor

signaling pathway inhibitors, and epigenetic modulators is being tested.

Anti-PD-L1 antibodies also mediate antitumor effects by ADCC,

which utilizes natural killer (NK) effector cells (Chap. 349). Indeed,

a number of checkpoint inhibitor molecules have been found to be

expressed on NK cells including CTLA-4, PD-1, LAG-3, TIGIT, and

TIM-3 (Fig. 350-1; see also Chap. 349, Table 349-1). A new field of

work is to target NK cells with existing checkpoint inhibitors and with

antibodies against an NK-specific inhibitory molecule, NKG2A, that

are designed release NK cells to kill tumor cells. One such anti-NKG2A

antibody, monalizumab, has entered human clinical trials. NK cells

also express natural cytotoxicity-activating receptors including NKp30,

NKp44, and NKp46 receptors (Chap. 349). Engagement of natural

cytotoxicity-activating receptors in concert with the NK FcγRIII

(CD16) and antibody against a tumor antigen also can enhance NK cell

targeting of tumor antigens and is in preclinical development.

CHIMERIC ANTIGEN RECEPTOR T CELLS

Chimeric antigen receptor (CAR) T cells are synthetic hybrid receptors created by recombinant techniques that combine an extracellular domain, usually derived from an antibody single-chain variable

fragment (scFv), with intracellular signaling domains from activating

co-stimulatory molecules (from endogenous TCRs, CD28, or 4-1BB)

that allow for retargeting of T cells to antigens on malignant cells

(Fig. 350-3). A CAR T cell targeting the CD19 molecule on malignant

B cells provided the first and most promising therapeutic results in

the treatment of B-cell malignancies, with complete response rates of

70–90%. CAR T cells targeting the NY-ESO antigen on sarcoma cells

have induced remissions in patients with synovial cell sarcoma. CAR

T cells targeting B-cell maturation antigen (BCMA) on myeloma cells

have also induced clinical responses. The CAR T-cell strategy is being

developed for targeting solid tumors and modified as universal CAR T

cells to overcome the need for MHC matching with T CAR recipients.

One such strategy is to modify T cells to release cytokine, express

co-stimulatory ligands, or secrete checkpoint-blocking single-chain

variable fragment (scFvs). The next generation of CAR T cells are

known as T cells redirected for universal cytokine-mediated killing

(TRUCKs). Cytokine-secreting tumor-specific T cells could harness