Mechanisms of Regulation and Dysregulation of the Immune System

2705CHAPTER 350

the adjuvant effect of recombinant cytokines by local delivery to the

tumor to decrease cytokine side effects of excess inflammation, termed

cytokine release syndrome, that can be seen with CAR T-cell therapy.

MECHANISMS OF IMMUNE

DYSREGULATION IN AUTOIMMUNE

DISEASE

Autoimmune diseases occur in ~5% of people and are caused by

immune dysregulation from breakdowns in immune tolerance. A complex array of immune checkpoints are involved in the maintenance of

immune homeostasis and, when mutated, can result in autoimmune

syndromes (Tables 350-1 and 350-3). Central tolerance for deletion of

autoreactive T cells or modification of their TCRs occurs in the thymus, and for B cells with self-reactive B-cell receptors, central deletion

occurs in bone marrow. Peripheral tolerance occurs in lymph nodes,

spleen, and tissue-associated lymphoid tissue such as gastrointestinal

tract Peyer’s patches. The sites and modes of peripheral tolerance are

varied and reflect the complex cellular and cytokine interactions that

occur in mediation of T- and B-cell adaptive immunity (Chap. 349).

While B- and T-cell deletion can occur in the periphery, tolerance

can also occur with cell inactivation termed anergy, a state of immune

responsiveness following contact with antigen. T- and B-cell responses

are also dampened in the periphery by Tregs producing TGF-β and

IL-10. The result of immune dysregulation in autoimmune disease is

the production of a myriad of antibodies against self-antigens (autoantibodies), many of which are pathogenic for the clinical manifestations

of the autoimmune disease (see Chap. 349, Table 349-10).

TABLE 350-2 Summary of the Tumor Types for Which Immune Checkpoint Blockade Therapies Are Approved by the U.S. Food and Drug

Administration (FDA)

TUMOR TYPE THERAPEUTIC AGENT TARGET FDA APPROVAL YEAR

Melanoma Ipilimumab CTLA-4 2011

Melanoma Nivolumab PD-1 2014

Melanoma Pembrolizumab PD-1 2014

Non-small-cell lung cancer Nivolumab PD-1 2015

Non-small-cell lung cancer Pembrolizumab PD-1 2015

Melanoma (BRAF wild-type) Ipilimumab + nivolumab CTLA-4 + PD-1 2015

Melanoma (adjuvant) Ipilimumab CTLA-4 2015

Renal cell carcinoma Nivolumab PD-1 2015

Hodgkin’s lymphoma Nivolumab PD-1 2016

Urothelial carcinoma Atezolizumab PD-L1 2016

Head and neck squamous cell carcinoma Nivolumab PD-1 2016

Head and neck squamous cell carcinoma Pembrolizumab PD-1 2016

Melanoma (any BRAF status) Ipilimumab + nivolumab CTLA-4 + PD-1 2016

Non-small-cell lung cancer Atezolizumab PD-L1 2016

Hodgkin’s lymphoma Pembrolizumab PD-1 2017

Merkel cell carcinoma Avelumab PD-L1 2017

Urothelial carcinoma Avelumab PD-L1 2017

Urothelial carcinoma Durvalumab PD-L1 2017

Urothelial carcinoma Nivolumab PD-1 2017

Urothelial carcinoma Pembrolizumab PD-1 2017

MSI-high or MMR-deficient solid tumors of any histology Pembrolizumab PD-1 2017

MSI-high, MMR-deficient metastatic colorectal cancer Nivolumab PD-1 2017

Pediatric melanoma Ipilimumab CTLA-4 2017

Hepatocellular carcinoma Nivolumab PD-1 2017

Gastric and gastroesophageal carcinoma Pembrolizumab PD-1 2017

Non-small-cell lung cancer Durvalumab PD-L1 2018

Renal cell carcinoma Ipilimumab + nivolumab CTLA-4 + PD-1 2018

Note: A summary of the tumor indications, therapeutic agents, and year of FDA approval for immune checkpoint blockade therapies. FDA approval includes regular approval

and accelerated approval granted as of May 2018. Ipilimumab is an anti-CTLA-4 antibody. Nivolumab and pembrolizumab are anti-PD-1 antibodies. Atezolizumab, avelumab,

and durvalumab are anti-PD-L1 antibodies. Tumor type reflects the indications for which treatment has been approved. Only the first FDA approval granted for each broad

tissue type or indication for each therapeutic agent is noted. In cases where multiple therapies received approval for the same tumor type in the same year, agents are

listed alphabetically.

Abbreviations: BRAF, v-raf murine sarcoma viral oncogene, homolog B1; MMR, mismatch repair; MSI, microsatellite instability.

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

Cancer cell

T cell

A

B

B cell cancer

CAR T cell

TCR signaling

motif (CD3z)

costim. motif

(CD28 or 4-1BB)

anti-CD19

scFV

Target antigen:

CD19

Output

• Killing

• Proliferation

• Cytokines

Chimeric antigen

receptor (CAR)

NY-ESO

antigen

T-cell receptor

(TCR)

Chimeric antigen

receptor (CAR)

Antigen

MHC complex CAR antigen

CD19

Anti-CD19 CAR

FIGURE 350-3 Platforms for redirecting T cells to cancer. A. T-cell receptors (TCRs;

e.g., anti-NY-ESOI) or chimeric antigen receptors (CARs; e.g., anti-CD19 CAR).

B. CAR structure includes an extracellular antigen recognition domain fused to

intracellular TCR signaling domains (CD3z) and co-stimulatory domains (e.g., CD28

or 4-1BB). (Reproduced with permission from WA Lim, CH June: The principles of

engineering immune cells to treat cancer. Cell 168:724, 2017.)

2706 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Tregs are CD4 and CD8 T cells that downmodulate B- and T-cell

responses in peripheral lymphoid tissues to prevent autoimmune diseases, and the transcriptional regulator FOXP3 is centrally involved in

the establishment of the Treg phenotype. Mutations in genes that lead

to loss of Tregs or their function result in autoimmune and inflammatory syndromes (Table 350-1). Mutations in FOXP3 lead to an X-linked

syndrome characterized by immune dysregulation, polyendocrinopathy, and enteropathy (IPEX). Similarly, mutations in the CD25 (IL-2

receptor α) molecule expressed on Tregs lead to enteropathy, dermatitis,

other manifestations of autoimmunity, and susceptibility to infections.

Mutations in the checkpoint inhibitor T-cell molecule CTLA-4—also

expressed on Tregs—leads to loss of Treg function and results in multiple autoimmune syndromes in humans depending on the CTLA-4

mutation. In mice, knockout of the ctla4 gene leads to massive uncontrolled lymphoproliferation and early death. Finally, mutations in

the lipopolysaccharide (lipopolysaccharide-responsive and beige-like

anchor [LRBA]) protein cause a syndrome in infants characterized by

enteritis, hypogammaglobulinemia, and autoimmune cytopenias.

Chronic viral infections can perturb Treg number and function.

In HIV-1 infection, chronic antigenic stimulation leads to shifts in

the B-cell repertoire toward an autoimmune permissive state, with

increased numbers of autoreactive B cells and decreased CD4+ Tregs

leading to serum autoantibodies or clinical manifestations of autoimmune disease in ~50% of untreated HIV-1-infected individuals.

In addition to checkpoint inhibition for cancer immunotherapy,

monoclonal antibodies can be used for immune modulation to correct

dysregulated immunity in autoimmune diseases to restore normal levels of immunoregulatory tolerance control. Monoclonal therapies have

been developed and successfully used for the treatment of autoimmune

and inflammatory diseases (Table 350-4). Some of the monoclonal

antibodies such as anti-CD20 (rituximab) have also been used for the

treatment of B-cell malignancies. CTLA-4-Fc has been developed to

prevent CD28-induced T-cell activation, resulting in immune suppression for rheumatoid arthritis (RA) and transplantation. TNF-α has

been shown to play a central role in RA pathogenesis, and anti-TNF-α

antibodies have been successful in treatment of RA and are approved

for other autoimmune syndromes including other forms of arthritis,

inflammatory bowel disease, and psoriasis. Antibodies against α4 integrin block the migration of α4β7+ T cells to the gastrointestinal tract

and are used to treat inflammatory bowel disease (IBD). The TH17

cytokine IL-17 has been found to be overproduced in psoriasis, and

monoclonal anti-IL-17 antibody therapy for psoriasis is now approved

by the FDA (Chap. 57).

Tregs are therapeutic candidates for restoring immune tolerance in

autoimmune and autoinflammatory diseases, with the prospect of reducing or replacing immunosuppressive drugs. Like CAR T cells, Treg therapy involves expanding autologous Treg cells in vitro and reinfusing them

into individuals with autoimmune or inflammatory diseases. To make

Treg therapy more targeted for suppression of antigen-specific immune

responses, CAR T technology is being used to redirect Tregs to pathogenic T and B cells. Treg cellular therapy is in human clinical trials for

the treatment of graft-versus-host disease in the setting of transplantation

and for prevention of progression of type 1 diabetes mellitus (Chap. 404).

IMMUNE DYSREGULATION IN AGING

Aging of the immune system in humans is characterized by decline in

both innate and adaptive immunity. Aging is also paradoxically associated

with a state of chronic inflammation, termed “inflammaging,” with an

increased risk of autoimmune disease. Aging is associated with reduced

NK cell function, reduced monocyte/macrophage immune cell expression

of toll-like receptors, reduced chemotaxis and phagocytosis, and reduced

MHC expression and signaling. Other phagocytic cells such as polymorphonuclear cells are similarly dysfunctional. Dendritic cells in aged individuals are present in reduced numbers with impaired antigen-presenting

function and signaling. Adaptive immunity is similarly impaired with

decreased antibody repertoire breadth, decrease in number of B cells, and

decrease in B-cell responses to specific antigens. Similarly, T-cell responses

to antigen are decreased, such as to seasonal influenza vaccination.

Aging is characterized by accumulation of senescent cells in many

tissues that secrete inflammatory cytokines, chemokines, and other

inflammatory mediators. The best example of the role of enhanced

cytokine production in the “inflammaging” syndrome is in thymic

atrophy, which is a major event contributing to age-associated immune

system decline. During life, the thymus decreases in size and naïve

T-cell output decreases; beginning with puberty, thymocytes progressively decrease in number, such that after ~50 years of age, ~90% of

thymocytes have been replaced by adipocytes in the thymus perivascular space. Thymic adipocytes produce leukemia inhibitory factor,

oncostatin M, IL-6, and stem cell factor (SCF). Administration of

these cytokines to young mice induces thymic atrophy, demonstrating that these thymosuppressive cytokines actively induce thymocyte

loss. Adipocytes in other sites also produce inflammatory cytokines,

contributing to tissue senescence. Finally, respiratory failure due to

SARS-CoV-1, Middle Eastern respiratory syndrome, or SARS-CoV-2

infection is associated with a cytokine release syndrome with IL-6

overproduction, which occurs most frequently in older individuals.

TABLE 350-3 Immune Tolerance Checkpoints in T- and B-Cell Immunity

CENTRAL TOLERANCE PERIPHERAL TOLERANCE

THYMUS PERIPHERAL LYMPHOID TISSUES

– TCR editing by V(D)J – B and T cell anergy and inhibitory signaling (CTLA-4, PD-1 and other checkpoint molecules)

– Thymic negative selection – TCR or BCR induction of BIM

– T cell anergy and inhibitory signaling – T cell competition for IL-2, IL-7, IL-15 and peptide-MHC

– T regulatory cell differentiation – B cell competition for survival cytokine BAFF

– T cell growth dependence on CD28 ligands and other co-stimulatory molecules

– Elimination of antigen-bearing dendritic cells by activated T cells producing perforin or FasL

– Suppression of T and B cell responses by T regulatory cells and TGFβ, IL-10

– T cell death by FasL

– Regulation of T follicular helper cell differentiation and function

BONE MARROW – B cell growth dependence on BCR ligands

– Immature B cell maturation arrest – B cell growth dependence on TCR ligands

– BCR editing by V(D)J recombination – B cell death by FasL on T cells

– Immature B cell deletion – BCR modulation of plasma cell differentiation

– BCR-induced death of germinal center B cells

– Germinal center B cell dependence on T follicular helper cells (CD40L, IL-21)

Abbreviations: BAFF, B cell activating factor; BCR, B cell receptor; BIM, Bcl-2-like protein 11; Fas; TGFβ = T cell growth factor beta; FasL = Fas ligand that binds to the death

receptor; MHC, major histocompatibility complex; TCR, T cell receptor; V(D)J, variable, diversity, joining regions of antibody V region.

Source: Adapted from CG Goodnow: Multistep pathogenesis of autoimmune disease. Cell 130:25, 2007.

Mechanisms of Regulation and Dysregulation of the Immune System

2707CHAPTER 350

TABLE 350-4 Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in Malignanciesa

TARGET

MOLECULE FUNCTION

FDA-APPROVED mAbs, TRAPS, AND

BISPECIFIC mAbs

AUTOIMMUNE/

INFLAMMATORY MALIGNANCY OTHER/COMMENTS

CD52 Marker of T and B

lymphocyte subsets

Alemtuzumab (Lemtrada) Multiple sclerosis Chronic

lymphocytic

leukemia

Trade name changed from

Campath-1H (cancer) to

Lemtrada (multiple sclerosis)

Humanized IgG1k

CD25 Alpha-chain of the IL-2

receptor

Basiliximab (Simulect) Multiple sclerosis Basiliximab: chimeric mouse/

human IgG1k

Daclizumab (Zenapax) Transplant rejection Daclizumab: humanized IgG1

CD20 Participates in B-cell

differentiation

Obinutuzumab (Gazyva)

Ibritumomab tiuxetan (Zevalin)

Rheumatoid arthritis B-cell

malignancies

Obinutuzumab is the first

approved glycoengineered IgG1

mAb with enhanced ADCC

Tositumomab (Bexxar)a

 Ofatumumab

(Arzerra) Rituximab (Rituxan)

Rituximab is chimeric mouse/

human IgG1k

Ibritumomab tiuxetan and

tositumomab are radioconjugates that can be used

when tumors stop responding to

the anti-CD20 mAbs

Ibritumomab and tositumomab

are mouse IgG2a

CD80/CD86 Provide co-stimulatory

signals necessary for T-cell

activation and survival;

ligand trap prevents

activation of CD28 immune

checkpoint resulting in

immune suppression

Belatacept (Nulojix)

Abatacept (Orencia)

(both CTLA-4-Fc fusion proteins)

Rheumatoid arthritis

Transplant rejection

TNF-α Inflammatory cytokine that

drives multiple autoimmune

diseasesa

Adalimumab (Humira)

Certolizumab pegol (Cimzia)

Golimumab (Simponi)

Infliximab (Remicade)

Etanercept (Enbrel)

There are more than 20 anti-TNF

biosimilars in various stages of

development.

Already approved are infliximab

biosimilars (Remsima, Inflectra, Flixabi),

etanercept biosimilars (Erelzi, Benepali),

and adalimumab biosimilars (Amjevita).

This field will change very rapidly as

many dossiers are now under regulatory

scrutiny.

Biosimilars are given a suffix, e.g.,

etanercept-szzs (Erelzi)

Crohn’s disease,

ulcerative colitis,

RA, juvenile

idiopathic arthritis,

psoriatic arthritis,

ankylosing

spondylitis,

plaque psoriasis,

hidradenitis

suppurativa, uveitis

Not all TNF blockers are

approved for all indications

Drugs in italics are biosimilars:

adalimumab, infliximab,

infliximab, Inflectra,

adalimumab-atto are IgG1k

mAbs; certolizumab pegol is

a pegylated Fab fragment;

etanercept is a soluble Fc:TNF

receptor trap that binds TNF

(there is one biosimilar). At least

four biosimilar TNF blockers

have been approved in the EU

(two each for infliximab and

etanercept)

VEGF Cytokine that stimulates

vasculogenesis

and angiogenesis.

Overproduced in some

inflammatory disorders and

tumors to induce increased

blood supply.

Bevacizumab (Avastin)

Ramucirumab (Cyramza)

Aflibercept (Eylea/Zaltrap)

Ranibizumab (Lucentis)

Age-related

macular

degeneration,

macular edema,

diabetic macular

edema, diabetic

retinopathy

Colorectal cancer,

nonsquamous

NSCLC,

breast cancer,

glioblastoma, renal

cell carcinoma,

gastric cancer or

gastroesophageal

junction

adenocarcinoma

Bevacizumab and ramucirumab

are IgG1 mAbs for cancer

therapy (ramucirumab was

derived from phage display);

ranibizumab is a Fab fragment

(single arm binder). It has a

short half-life if administered

intravenously, but it is stable

when locally injected into the

eye. Aflibercept is a ligand trap

with optical (Eylea) and cancer

(Zaltrap) applications.

IL-4 receptor

alpha subunit

Receptor that mediates

IL-4 and IL-13-induced

inflammation

Dupilumab (Dupixent) Atopic dermatitis

(eczema), steroiddependent asthma

IgE Binds to mast cells,

basophils, and other cells

that express Fc-epsilon

receptor and induces

release of inflammatory

cytokines

Omalizumab (Xolair) Asthma IgG1k mAb also used off-label

to treat IgE-related conditions

(allergic rhinitis, drug allergies,

other)

(Continued)

2708 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 350-4 Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in Malignanciesa

TARGET

MOLECULE FUNCTION

FDA-APPROVED mAbs, TRAPS, AND

BISPECIFIC mAbs

AUTOIMMUNE/

INFLAMMATORY MALIGNANCY OTHER/COMMENTS

Alpha-4

integrin

Alpha-4 integrin facilitates

exit of inflammatory cells

from blood into intestine

or across the blood-brain

barrier

Vedolizumab (Entyvio)

Natalizumab (Tysabri)

Multiple sclerosis,

Crohn’s disease,

and ulcerative

colitis

IgG4 natalizumab therapy has

been associated with PML

caused by John Cunningham

virus in immunocompromised

patients. IgG1k vedolizumab may

not be associated with PML.

Complement

C5

Inhibits complement

cascade

Eculizumab (Solaris) Prevents

destruction of

red blood cells

by activated

complement

(paroxysmal

nocturnal

hemoglobinuria)

IgG2/4 mAb; most expensive

drug in the world ($409,500

annually)

P40 subunit

of IL-12 and

IL-23

Mutations in cryopyrin lead

to overproduction of IL-1

and inflammatory disease;

IL-1 also drives other

inflammatory diseases

Canakinumab (Ilaris)

Rilonacept (Arcalyst)a

Rare inflammatory

syndromes, active

juvenile arthritis,

gouty arthritis

Canakinumab is an IgG1k

mAb; rilonacept is an IL-1 trap

designed from the IL-1R fused

with human mAb Fc region.

IL-6 Overexpression of IL-6 is

associated with multiple

malignancies

Siltuximab (Sylvant) Pseudomalignancy:

Castleman’s

disease (similar to

lymphoma)

Murine/human chimeric IgG1κ

IL-6R (IL-6

receptor)

Current approvals based

on role of IL-6 in promoting

inflammatory autoimmune

disease

Tocilizumab (Actemra) Rheumatoid arthritis,

polyarticular

juvenile arthritis,

juvenile idiopathic

arthritis

Human/mouse chimeric mAb

with initial approval for efficacy

in RA after failure of TNF blocker

BAFF (tumor

necrosis

factor

superfamily

member 13b)

Role in proliferation and

differentiation of B cells

Belimumab (Benlysta) Systemic lupus

erythematosus

IgG1-γ/λ

SLAMF7/

CD319

SLAMF7 triggers

the activation and

differentiation of a wide

variety of immune cells

(innate and adaptive

immune response) perhaps

primarily mediated by

natural killer cells and

myeloma cells

Elotuzumab (Empliciti) Multiple myeloma This IgG1k mAb is thought to

activate SLAMF7 receptor and

to have a secondary mechanism

of mediating ADCC vs multiple

myeloma cells

IL-5 Induces differentiation and

survival of eosinophils

Reslizumab (Cinqair)

Mepolizumab (Nucala)

Asthma Both IgG1k mAbs

IL-17A Inflammatory cytokine Ixekizumab (Taltz)

Secukinumab (Cosentyx)

Plaque psoriasis,

ankylosing

spondylitis

Ixekizumab is an IgG4;

secukinumab is an IgG1k

a

Approved for use in United States only.

Note: An actively updated summary of MAb approvals can be found at www.antibodysociety.org. mAbs can be murine, chimeric (human Fc region), humanized, or human;

traps are derived from receptors and compete with natural receptor for binding target; bispecific mAbs are engineered to bind to two different targets simultaneously

(usually to bring immune cell into contact with target cell, thereby triggering target cell killing). Antibody-drug conjugate (X): toxin or radioisotope attached to mAb to

increase efficacy. Agents approved for use in the United States only are noted; others are approved in both United States and United Kingdom.

Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; BAFF, B-cell activating factor; CTLA-4, cytotoxic T-cell lymphocyte-associated protein-4; EU, European

Union; Ig, immunoglobulin; FDA, U.S. Food and Drug Administration; IL, interleukin; mAb, monoclonal antibody; NSCLC, non-small-cell lung cancer; PML, progressive

multifocal leukoencephalopathy; RA, rheumatoid arthritis; SLAMF7, signaling lymphocyte activation molecule family member 7; TNF, tumor necrosis factor; VEGF, vascular

endothelial growth factor.

Source: Republished with permission of Royal College of Physicians, from Developments in therapy with monoclonal antibodies and related proteins, HM Shepard et al,

17:220, 2017; permission conveyed through Copyright Clearance Center, Inc.

(Continued)

■ FURTHER READING

Ferreira LMR et al: Next-generation regulatory T cell therapy Nat

Rev Drug Discov 18:749, 2019.

Goodnow CG: Multistep pathogenesis of autoimmune disease. Cell

130:25, 2020.

Lim WA, June CH: The principles of engineering immune cells to treat

cancer. Cell 168:724, 2017.

Schildberg FA et al: Coinhibitory pathways in the B7-CD28

ligand-receptor family. Immunity 44:955, 2016.

Sharma P, Allison JP: The future of immune checkpoint therapy.

Science 348:5661, 2015.

Sharma P, Allison JP: Dissecting the mechanisms of immune checkpoint therapy. Nature Rev Immunol 20:75, 2020.

Sharpe A, Pauken KE: The diverse functions of the PD-1 pathway. Nat

Rev Immunol 18:153, 2018.

Wei SC et al: Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069, 2018.

Primary Immune Deficiency Diseases

2709CHAPTER 351

Immunity isintrinsic to life and an important tool in the fight forsurvival

against pathogenic microorganisms. The human immune system can be

divided into two major components: the innate immune system and the

adaptive immune system (Chap. 349). The innate immune system provides the rapid triggering of inflammatory responses based on the recognition (at the cell surface or within cells) of either molecules expressed

by microorganisms or molecules that serve as “danger signals” released

by cells under attack. These receptor/ligand interactions trigger signaling

events that ultimately lead to inflammation. Virtually all cell lineages

(not just immune cells) are involved in innate immune responses; however, myeloid cells (i.e., neutrophils and macrophages) play a major role

because of their phagocytic capacity. The adaptive immune system operates by clonal recognition of antigens followed by a dramatic expansion

of antigen-reactive cells and execution of an immune effector program.

Most of the effector cells die off rapidly, whereas memory cells persist.

Although both T and B lymphocytes recognize distinct chemical moieties and execute distinct adaptive immune responses, the latter is largely

dependent on the former in generating long-lived humoral immunity.

Adaptive responses utilize components of the innate immune system;

for example, the antigen-presentation capabilities of dendritic cells help

to determine the type of effector response. Not surprisingly, immune

responses are controlled by a series of regulatory mechanisms.

Hundreds of gene products have been characterized as effectors or

mediators of the immune system (Chap. 349). Whenever the expression

orfunction of one of these productsis genetically impaired (provided the

function is nonredundant), a primary immunodeficiency (PID) occurs.

PIDs are genetic diseases with primarily Mendelian inheritance.

More than 450 conditions have now been described, and deleterious

mutations in ~420 genes have been identified. The overall prevalence

of PIDs has been estimated in various countries at 5–10 per 100,000

individuals; however, given the difficulty in diagnosing these rare and

complex diseases, this figure is probably an underestimate. PIDs can

involve all possible aspects of immune responses, from innate through

adaptive, cell differentiation, and effector function and regulation. For

the sake of clarity, PIDs should be classified according to (1) the arm

of the immune system that is defective and (2) the mechanism of the

defect (when known). Table 351-1 classifies the most prevalent PIDs

according to this manner of classification; however, one should bear

in mind that the classification of PIDs sometimes involves arbitrary

decisions because of overlap and, in some cases, lack of data.

The consequences of PIDs vary widely as a function of the molecules

that are defective. This concept translates into multiple levels of vulnerability to infection by pathogenic and opportunistic microorganisms,

ranging from extremely broad (as in severe combined immunodeficiency [SCID]) to narrowly restricted to a single microorganism (as in

Mendelian susceptibility to mycobacterial disease [MSMD]). The locations of the sites of infection and the causal microorganisms involved

will thus help physicians arrive at proper diagnoses. PIDs can also lead

to immunopathologic responses such as allergy (as in Wiskott-Aldrich

syndrome [WAS]), lymphoproliferation, and autoimmunity. A combination of recurrent infections, inflammation, and autoimmunity can

be observed in a number of PIDs, thus creating obvious therapeutic

challenges. Finally, some PIDs increase the risk of cancer, notably but

not exclusively lymphocytic cancers, for example, lymphoma.

DIAGNOSIS OF PRIMARY

IMMUNODEFICIENCIES

The most frequent symptom prompting the diagnosis of a PID is the

presence of recurrent or unusually severe infections. As mentioned

above, recurrent allergic or autoimmune manifestations may also alert

351 Primary Immune

Deficiency Diseases

Alain Fischer

TABLE 351-1 Classification of Primary Immune Deficiency Diseases

Deficiencies of the Innate Immune System

• Phagocytic cells:

- Impaired production: severe congenital neutropenia (SCN)

- Asplenia

- Impaired adhesion: leukocyte adhesion deficiency (LAD)

- Impaired killing: chronic granulomatous disease (CGD)

• Innate immunity receptors and signal transduction:

- Defects in Toll-like receptor signaling

- Mendelian susceptibility to mycobacterial disease

• Complement deficiencies:

- Classical, alternative, and lectin pathways

- Lytic phase

Deficiencies of the Adaptive Immune System

• T lymphocytes:

- Impaired development

- Impaired survival,

migration, function

Severe combined immune deficiencies (SCIDs)

DiGeorge’s syndrome

Combined immunodeficiencies

Hyper-IgE syndrome (autosomal dominant)

DOCK8 deficiency

CD40 ligand deficiency

Wiskott-Aldrich syndrome

Ataxia-telangiectasia and other DNA repair

deficiencies

• B lymphocytes:

- Impaired development

- Impaired function

XL and AR agammaglobulinemia

Hyper-IgM syndrome

Common variable immunodeficiency (CVID)

IgA deficiency

Regulatory Defects

• Innate immunity

• Adaptive immunity

Autoinflammatory syndromes (outside the

scope of this chapter)

Severe colitis

Hemophagocytic lymphohistiocytosis (HLH)

Autoimmune lymphoproliferation syndrome

(ALPS)

Autoimmunity and inflammatory diseases

(IPEX, APECED)

Abbreviations: APECED, autoimmune polyendocrinopathy candidiasis ectodermal

dysplasia; AR, autosomal recessive; IPEX, immunodysregulation polyendocrinopathy

enteropathy X-linked syndrome; XL, X-linked.

the physician to a possible diagnosis of PID. In such cases, a detailed

account of the subject’s personal and family medical history should

be obtained. It is of the utmost importance to gather as much medical

information as possible on relatives and up to several generations of

ancestors. In addition to the obvious focus on primary symptoms, the

clinical examination should evaluate the size of lymphoid organs and,

when appropriate, look for the characteristic signs of a number of complex syndromes that may be associated with a PID.

The performance of laboratory tests should be guided to some

extent by the clinical findings. Infections of the respiratory tract (bronchi, sinuses) mostly suggest a defective antibody response. In general,

invasive bacterial infections can result from complement deficiencies,

signaling defects of innate immune responses, asplenia, or defective

antibody responses. Viral infections, recurrent Candida infections, and

opportunistic infections are generally suggestive of impaired T-cell

immunity. Skin infections and deep-seated abscesses primarily reflect

innate immune defects (such as chronic granulomatous disease);

however, they may also appear in the autosomal dominant hyper-IgE

syndrome. Table 351-2 summarizes the laboratory tests that are most

frequently used to diagnose a PID. More specific tests (notably genetic

tests) are then used to make a definitive diagnosis. Genomic tools now

allow us to more efficiently track genetic defects through usage of gene

panel resequencing and/or whole exome/genome sequencing.

2710 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

The PIDs discussed below have been grouped together according to the affected cells and the mechanisms involved (Table 351-1,

Fig. 351-1).

PRIMARY IMMUNODEFICIENCIES OF THE

INNATE IMMUNE SYSTEM

PIDs of the innate immune system are relatively rare and account for

~10% of all PIDs.

■ SEVERE CONGENITAL NEUTROPENIA

Severe congenital neutropenia (SCN) consists of a group of inherited

diseases that are characterized by severely impaired neutrophil counts

(<500 polymorphonuclear leukocytes [PMN]/μL of blood). The condition is usually manifested from birth. SCN may also be cyclic (with

a 3-week periodicity), and other neutropenia syndromes can also be

intermittent. Although the most frequent inheritance pattern for SCN

is autosomal dominant, autosomal recessive and X-linked recessive

conditions also exist. Bacterial infections at the interface between

the body and the external milieu (e.g., the orifices, wounds, and the

respiratory tract) are common manifestations. Bacterial infections can

rapidly progress through soft tissue and are followed by dissemination

in the bloodstream. Severe visceral fungal infections can also ensue.

The absence of pus is a hallmark of this condition.

Diagnosis of SCN requires examination of the bone marrow. Most

SCNs are associated with a block in granulopoiesis at the promyelocytic stage (Fig. 351-1). SCN has multiple etiologies, and to date,

mutations in 21 different genes have been identified. Most of these

mutations result in isolated SCN, whereas others are syndromic (Chap.

64). The most frequent forms of SCN are caused by the premature cell

death of granulocyte precursors, as observed in deficiencies of GFI1,

HAX1, and elastase 2 (ELANE), with the latter accounting for 50%

of SCN sufferers. Certain ELANE mutations cause cyclic neutropenia

syndrome. A gain-of-function mutation in the WASP gene (see the

Neutrophil Phagocytosis

Phagocytosis

Killing

ROS production

Killing

ROS production

Adhesion

Migration

HSC CMP

MB

SCN WHIM LAD CGD

CGD

MSMD

GM

prog.

Mono

blast

Pro mono

Pro myelo. myelo.

Monocyte

Dendritic cells

Tissue macrophages

Bone Marrow Blood Tissue

GATA2 deficiency

FIGURE 351-1 Differentiation of phagocytic cells and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common myeloid

progenitors (CMPs) and then granulocyte-monocyte progenitors (GM prog.), which, in turn, differentiate into neutrophils (MB: myeloblasts; Promyelo: promyelocytes; myelo:

myelocytes) or monocytes (monoblasts and promonocytes). Upon activation, neutrophils adhere to the vascular endothelium, transmigrate, and phagocytose the targets.

Reactive oxygen species (ROS) are delivered to the microorganism-containing phagosomes. Macrophages in tissues kill using the same mechanism. Following activation

by interferon γ (not shown here), macrophages can be armed to kill intracellular pathogens such as mycobacteria. For sake of simplicity, not all cell differentiation stages

are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. CGD, chronic granulomatous diseases; GATA2, zinc finger

transcription factor; LAD, leukocyte adhesion deficiencies; MSMD, Mendelian susceptibility to mycobacterial disease; SCN, severe congenital neutropenia; WHIM, warts,

hypogammaglobulinemia, infections, and myelokathexis.

TABLE 351-2 Tests Most Frequently Used to Diagnose a Primary

Immune Deficiency (PID)

TEST INFORMATION PID DISEASE

Blood cell counts and

cell morphology

Neutrophil countsa

Lymphocyte countsa

Eosinophilia

Howell-Jolly bodies

↓ Severe congenital

neutropenia, ↑↑ LAD

T-cell ID

WAS, hyper-IgE syndrome

Asplenia

Chest x-ray Thymic shadow

Costochondral junctions

SCID, DiGeorge’s syndrome

Adenosine deaminase

deficiency

Bone x-ray Metaphyseal ends Cartilage hair hypoplasia

Immunoglobulin

serum levels

IgG, IgA, IgM

IgE

B-cell ID

Hyper-IgE syndrome, WAS,

T-cell ID

Lymphocyte

phenotype

T, B lymphocyte counts T-cell ID,

agammaglobulinemia

Dihydrorhodamine

fluorescence (DHR)

assay

Nitroblue tetrazolium

(NBT) assay

Reactive oxygen species

production by PMNs

Chronic granulomatous

disease

CH50, AP50 Classic and alternative

complement pathways

Complement deficiencies

Ultrasonography of

the abdomen

Spleen size Asplenia

a

Normal counts vary with age. For example, the lymphocyte count is between 3000

and 9000/μL of blood below the age of 3 months and between 1500 and 2500/μL in

adults.

Abbreviations: ID, immunodeficiency; LAD, leukocyte adhesion deficiency; PMNs,

polymorphonuclear leukocytes; SCID, severe combined immunodeficiency; WAS,

Wiskott-Aldrich syndrome.

Primary Immune Deficiency Diseases

2711CHAPTER 351

section “Wiskott-Aldrich Syndrome” below) causes X-linked SCN,

which is also associated with monocytopenia.

As mentioned above, SCN exposes the patient to life-threatening,

disseminated bacterial and fungal infections. Treatment requires careful hygiene measures, notably in infants. Later in life, special oral and

dental care is essential, along with the prevention of bacterial infection

by prophylactic administration of trimethoprim/sulfamethoxazole.

Subcutaneous injection of the cytokine granulocyte colony-stimulating

factor (G-CSF) usually improves neutrophil development and thus prevents infection in most SCN diseases. However, there are two caveats:

(1) a few cases of SCN with ELANE mutation are refractory to G-CSF

and may require curative treatment via allogeneic hematopoietic stem

cell transplantation (HSCT); and (2) a subset of G-CSF-treated patients

carrying ELANE mutations are at a greater risk of developing acute

myelogenous leukemia associated (in most cases) with somatic gain-offunction mutations of the G-CSF receptor gene.

A few SCN conditions are associated with additional immune

defects involving leukocyte migration as observed in the warts,

hypogammaglobulinemia, infections, and myelokathexis (WHIM)

syndrome (gain-of-function mutation of the chemokine CXCR4) or in

moesin deficiency.

■ ASPLENIA

Primary failure of the development of a spleen is an extremely rare

disease that can be either syndromic (in Ivemark syndrome) or isolated

with an autosomal dominant expression; in the latter case, mutations

in the ribosomal protein SA were recently found. Due to the absence

of natural filtration of microbes in the blood, asplenia predisposes

affected individuals to fulminant infections by encapsulated bacteria.

Although most infections occur in the first years of life, cases may

also arise in adulthood. The diagnosis is confirmed by abdominal

ultrasonography and the detection of Howell-Jolly bodies in red blood

cells. Effective prophylactic measures (twice-daily oral penicillin and

appropriate vaccination programs) usually prevent fatal outcomes.

■ GATA2 DEFICIENCY

Recently, an immunodeficiency combining monocytopenia and dendritic and lymphoid (B and natural killer [NK]) cell deficiency

(DCML), also called monocytopenia with nontuberculous mycobacterial infections (mono-MAC), has been described as a consequence of a

dominant mutation in the gene GATA2, a transcription factor involved

in hematopoiesis. This condition also predisposes to lymphedema,

myelodysplasia, and acute myeloid leukemia. Infections (bacterial and

viral) are life-threatening, thus indicating, together with the malignant

risk, HSCT.

■ LEUKOCYTE ADHESION DEFICIENCY

Leukocyte adhesion deficiency (LAD) consists of three autosomal

recessive conditions (LAD I, II, and III) (Chap. 64). The most frequent

condition (LAD I) is caused by mutations in the β2 integrin gene; following leukocyte activation, β2 integrins mediate adhesion to inflamed

endothelium expressing cognate ligands. LAD III results from a defect

in a regulatory protein (kindlin, also known as Fermt 3) involved in

activating the ligand affinity of β2 integrins. The extremely rare LAD

II condition is the end result of a defect in selectin-mediated leukocyte

rolling that occurs prior to β2 integrin binding. There is a primary

defect in fucose transporter such that oligosaccharide selectin ligands

are missing in this syndromic condition.

Given that neutrophils are not able to reach infected tissues, LAD

renders the individual susceptible to bacterial and fungal infections

in a way that is similar to that of patients with SCN. LAD also causes

impaired wound healing and delayed loss of the umbilical cord. A

diagnosis can be suspected in cases of pus-free skin/tissue infections

and massive hyperleukocytosis (>30,000/μL) in the blood (mostly

granulocytes). Patients with LAD III also develop bleeding because the

β2 integrin in platelets is not functional. Use of immunofluorescence

and functional assays to detect β2 integrin can help form a diagnosis.

Severe forms of LAD may require HSCT, although gene therapy is also

now being considered. Neutrophil-specific granule deficiency (a very

rare condition caused by a mutation in the gene for transcription factor

C/EBPα) results in a condition that is clinically similar to LAD. Infrequent additional leukocyte motility defects have also been reported.

■ CHRONIC GRANULOMATOUS DISEASES

Chronic granulomatous diseases (CGDs) are characterized by impaired

phagocytic killing of microorganisms by neutrophils and macrophages

(Chap. 64). The incidence is ~1 per 200,000 live births. About 70% of

cases are associated with X-linked recessive inheritance versus autosomal inheritance in the remaining 30%. CGD causes deep-tissue bacterial and fungal abscesses in macrophage-rich organs such as the lymph

nodes, liver, and lungs. Recurrent skin infections (such as folliculitis)

are common and can prompt an early diagnosis of CGD. The infectious

agents are typically catalase-positive bacteria (such as Staphylococcus

aureus and Serratia marcescens) but also include Burkholderia cepacia,

pathogenic mycobacteria (in certain regions of the world), and fungi

(mainly filamentous molds, such as Aspergillus).

CGD is caused by defective production of reactive oxygen species

(ROS) in the phagolysosome membrane following phagocytosis of

microorganisms. It results from the lack of a component of NADPH

oxidase (gp91phox or p22phox) or of the associated adapter/activating

proteins (p47phox, p67phox, or p40phox) that mediate the transport

of electrons into the phagolysosome for creating ROS by interaction

with O2

. Under normal circumstances, these ROS either directly kill

engulfed microorganisms or enable the rise in pH needed to activate

the phagosomal proteases that contribute to microbial killing. Diagnosis of CGD is based on assays of ROS production in neutrophils and

monocytes (Table 351-2). As its name suggests, CGD is also a granulomatous disease. Macrophage-rich granulomas can often arise in the

liver, spleen, and other organs. These are sterile granulomas that cause

disease by obstruction (bladder, pylorus, etc.) or protracted inflammation (colitis, restrictive lung disease).

The management of infections in patients with CGD can be a complex process. The treatment of bacterial infections is generally based

on combination therapy with antibiotics that are able to penetrate into

cells. The treatment of fungal infections requires aggressive, long-term

use of antifungals. Inflammatory/granulomatous lesions are usually

steroid-sensitive, but often become glucocorticoid-dependent; liver

abscesses are best managed by administering antibiotics together with

glucocorticoids.

The treatment of CGD mostly relies on preventing infections. It

has been unambiguously demonstrated that prophylactic usage of

trimethoprim/sulfamethoxazole is both well tolerated and highly effective in reducing the risk of bacterial infection. Daily administration

of azole derivatives (notably itraconazole) also reduces the frequency

of fungal complications. It has long been suggested that interferon γ

administration is helpful, although medical experts continue to disagree over this controversial issue. Patients may do reasonably well

for some time with prophylaxis and careful management. However,

patients are at high risk lifelong of severe and persistent fungal infections and/or chronic inflammatory complications, leading to consideration of performing HSCT. Due to an increase in reported successes,

HSCT is now an established curative approach for CGD; however, the

risk-versus-benefit ratio must be carefully assessed on a case-by-case

basis. Gene therapy approaches are also being evaluated.

■ MENDELIAN SUSCEPTIBILITY TO

MYCOBACTERIAL DISEASE

This group of diseases is characterized by a defect in the interleukin-12

(IL-12)–interferon (IFN) γ axis (including IL-12p40, IL-12 receptor

[R] β1 and β2

, IFN-γ R1 and R2

, TYK2, STAT1, IRF8, and ISG515

deficiencies), which ultimately leads to impaired IFN-γ-dependent

macrophage activation. Both recessive and dominant inheritance

modes have been observed. The hallmark of this PID is a specific and

relatively narrow vulnerability to tuberculous and nontuberculous

mycobacteria. The most severe phenotype (as observed in complete

IFN-γ receptor deficiency) is characterized by disseminated infection

that can be fatal even when aggressive and appropriate antimycobacterial therapy is applied. In addition to mycobacterial infections, MSMD

2712 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

ZAP70

MHCII

STIM1

SCID

CLP

CD4

CD40L

SAP

ICOS

Th

B cells

Myeloid

NK cells

HSC

Orai1 HLH

γIFN, etc...

γIFN, etc...

IL4, etc...

DOCK 8

CMC

IL17, IL17F, IL17RA,

IL17RC, STAT1 gof

IL21, etc...

IL10, TGFβ, etc...

IL4, cytotoxicity

γIFN, etc...

Cytotoxicity

γIFN, TNF, etc... Tc

TH1

CD8

TH2

TFh

Treg

NKT

TH17 Orai1

STIM1

LAT

γδ

Thymus

MSMD

RORC

STAT3

ZAP70

TAP

IPEX

(Foxp3)

CD25,

STAT5b

XLP (SAP)

FIGURE 351-2 T-cell differentiation, effector pathways, and related primary immunodeficiencies (PIDs).

Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which, in turn, give

rise to the T-cell precursors that migrate to the thymus. The development of CD4+ and CD8+ T cells is shown.

Known T-cell effector pathways are indicated, that is, γδ cells, cytotoxic T cells (Tc), TH1, TH2, TH17, TFh (follicular

helper) CD4 effector T cells, regulatory T cells (Treg), and natural killer T cells (NKTs); abbreviations for PIDs

are contained in boxes. Vertical bars indicate a complete deficiency; broken bars a partial deficiency. DOCK8,

autosomal recessive form of hyper-IgE syndrome; HLH, hematopoietic lymphohistiocytosis; IL17F, IL17RA,

STAT1 (gof: gain of function), CMC (chronic mucocutaneous candidiasis), CD40L, ICOS, SAP deficiencies;

IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; LAT, linker for activation

of T cells; MHCII, major histocompatibility complex class II deficiency; MSMD, Mendelian susceptibility to

mycobacterial disease; Orai1, STIM1 deficiencies; RORC, RAR related orphan receptor C; SCID, severe combined

immunodeficiency; STAT3, autosomal dominant form of hyper-IgE syndrome; TAP, TAP1 and TAP2 deficiencies;

XLP, X-linked proliferative syndromes; ZAP70, zeta-associated protein deficiency.

patients (and particularly those with an IL-12/IL-12R deficiency) are

prone to developing Salmonella infections. Although MSMDs are very

rare, they should be considered in any patient with persistent mycobacterial infection. Treatment with IFN-γ may efficiently bypass an

IL-12/IL-12R deficiency. HSCT is a therapeutic option for the most

severe cases.

■ TOLL-LIKE RECEPTOR (TLR) PATHWAY

DEFICIENCIES

In a certain group of patients with early-onset, invasive Streptococcus

pneumoniae infections or (less frequently) Staphylococcus aureus or

other pyogenic infections, conventional screening for PIDs does not

identify the cause of the defect in host defense. It has been established

that these patients carry recessive mutations in genes that encode

essential adaptor molecules (IRAK4 and MYD88) involved in the

signaling pathways of the majority of known TLRs (Chap. 349).

Remarkably, susceptibility to infection appears to decrease after the

first few years of life—perhaps an indication that adaptive immunity

(once triggered by an initial microbial challenge) is then able to prevent

recurrent infections.

Certain TLRs (TLR-3, -7, -8, and -9) are involved in the recognition

of RNA and DNA and usually become engaged during viral infections.

Very specific susceptibility to herpes simplex encephalitis has been

described in patients with a deficiency in Unc93b (a molecule associated

with TLR-3, -7, -8, and -9 required for correct subcellular localization),

TLR-3, or associated signaling molecules TRIF, TBK1, and TRAF3,

resulting in defective type I IFN production. The fact that no other TLR

deficiencies have been found—despite extensive screening of patients

with unexplained, recurrent infections—strongly suggests that these

receptors are functionally redundant. Hypomorphic mutations in NEMO/IKK-γ (a member of the NF-κB complex, which is activated

downstream of TLR receptors) lead to a complex, variable immunodeficiency and a number

of associated features. Susceptibility to both

invasive, pyogenic infections and mycobacteria

may be observed in this particular setting.

Rare cases of predisposition to severe viral

infections(influenza, live measles vaccine) have

been found in patients with genetic defects in

IFN type I receptor and signaling pathways.

■ COMPLEMENT DEFICIENCY

The complement system is composed of a complex cascade of plasma proteins (Chap. 349)

that leads to the deposition of C3b fragments

on the surface of particles and the formation

of immune complexes that can culminate in

the activation of a lytic complex at the bacterial surface. C3 cleavage can be mediated

via three pathways: the classic, alternate, and

lectin pathways. C3b coats particles as part of

the opsonization process that facilitates phagocytosis following binding to cognate receptors.

A deficiency in any component of the classic

pathway (C1q, C1r, C1s, C4, and C2) can predispose an individual to bacterial infections

that are tissue-invasive or that occur in the

respiratory tract. Likewise, a C3 deficiency

or a deficiency in factor I (a protein that regulates C3 consumption, thus leading to a C3

deficiency due to its absence) also results in

the same type of vulnerability to infection.

It has recently been reported that a very rare

deficiency in ficolin-3 predisposes affected

individuals to bacterial infections. Deficiencies

in the alternative pathway (factors D and properdin) are associated with the occurrence of

invasive Neisseria infections.

Lastly, deficiencies of any complement component involved in the

lytic phase (C5, C6, C7, C8, and, to a lesser extent, C9) predispose

affected individuals to systemic infection by Neisseria. This is explained

by the critical role of complement in the lysis of the thick cell wall possessed by this class of bacteria.

Diagnosis of a complement deficiency relies primarily on testing

the status of the classic and alternate pathway via functional assays,

that is, the CH50 and AP50 tests, respectively. When either pathway

is profoundly impaired, determination of the status of the relevant

components in that pathway enables a precise diagnosis. Appropriate

vaccinations and daily administration of oral penicillin are efficient

means of preventing recurrent infections. It is noteworthy that several

complement deficiencies (in the classic pathway and the lytic phase)

may also predispose affected individuals to autoimmune diseases

(notably systemic lupus erythematosus; Chap. 356).

PRIMARY IMMUNODEFICIENCIES OF THE

ADAPTIVE IMMUNE SYSTEM

■ T LYMPHOCYTE DEFICIENCIES (TABLE 351-1,

FIGS. 351-2 AND 351-3)

Given the central role of T lymphocytes in adaptive immune responses

(Chap. 349), PIDs involving T cells generally have severe pathologic

consequences; this explains the poor overall prognosis and the need

for early diagnosis and the early intervention with appropriate therapy. Several differentiation pathways of T-cell effectors have been

described, one or all of which may be affected by a given PID (Fig.

351-2). Follicular helper CD4+ T cells in germinal centers are required

for T-dependent antibody production, including the generation of

Primary Immune Deficiency Diseases

2713CHAPTER 351

Ig class-switched, high-affinity antibodies. CD4+ TH1 cells provide

cytokine-dependent (mostly IFN-γ-dependent) help to macrophages

for intracellular killing of various microorganisms, including mycobacteria and Salmonella. CD4+ TH2 cells produce IL-4, IL-5, and IL-13 and

thus recruit and activate eosinophils and other cells required to fight

helminth infections. CD4+ TH17 cells produce IL-17 and IL-22 cytokines that recruit neutrophils to the skin and lungs to fight bacterial and

fungal infections. Cytotoxic CD8+ T cells can kill infected cells, notably

in the context of viral infections. In addition, certain T-cell deficiencies

predispose affected individuals to Pneumocystis jiroveci lung infections

early in life and to chronic gut/biliary duct/liver infections by Cryptosporidium and related genera later on in life. Lastly, naturally occurring

or induced regulatory T cells are essential for controlling inflammation

(notably reactivity to commensal bacteria in the gut) and autoimmunity. The role of other T-cell subsets with limited T-cell receptor (TCR)

diversity (such as γδTCR T cells or natural killer T [NKT] cells) in

PIDs is less well known; however, these subsets can be defective in certain PIDs, and this finding can sometimes contribute to the diagnosis

(e.g., NKT-cell deficiency in X-linked proliferative syndrome [XLP]).

T-cell deficiencies account for ~20% of all cases of PID.

Severe Combined Immunodeficiencies SCIDs constitute a

group of rare PIDs characterized by a profound block in T-cell development and thus the complete absence of these cells. The developmental block is always the consequence of an intrinsic deficiency. The

incidence of SCID is estimated to be 1 in 50,000 live births. Given the

severity of the T-cell deficiency, clinical consequences occur early in

life (usually within 3–6 months of birth). The most frequent clinical

manifestations are recurrent oral candidiasis, failure to thrive, and

protracted diarrhea and/or acute interstitial pneumonitis caused by P.

jiroveci (although the latter can also be observed in the first year of life

in children with B-cell deficiencies). Severe viral infections or invasive

bacterial infections can also occur. Patients may also experience complications related to infections caused by live vaccines (notably bacille

Calmette-Guérin [BCG]) that may lead not only to local and regional

infection but also to disseminated infection manifested by fever, splenomegaly, and skin and lytic bone lesions. A scaly skin eruption can

be observed in a context of maternal T-cell engraftment (see below).

A diagnosis of SCID can be suspected

based on the patient’s clinical history

and, possibly, a family history of deaths in

very young children (suggestive of either

X-linked or recessive inheritance). Lymphocytopenia is strongly suggestive of

SCID in >90% of cases (Table 351-2). The

absence of a thymic shadow on a chest

x-ray can also be suggestive of SCID.

An accurate diagnosis relies on precise

determination of the number of circulating T, B, and NK lymphocytes and

their subsets. T-cell lymphopenia may be

masked in some patients by the presence

of maternal T cells (derived from maternal-fetal blood transfers) that cannot be

eliminated. Although counts are usually

low (<500/μL of blood), higher maternal

T-cell counts may, under some circumstances, initially mask the presence of

SCID. Thus, screening for maternal cells

by using adequate genetic markers should

be performed whenever necessary. Inheritance pattern analysis and lymphocyte

phenotyping can discriminate between

various forms of SCID and provide guidance in the choice of accurate molecular

diagnostic tests (see below). To date, five

distinct causative mechanisms for SCID

(Fig. 351-3) have been identified. T-cell

quantification of receptor excision circles

(TREC) by using the Guthrie card is a reliable diagnostic test for newborn screening. It is now operational in the United States and several

other countries worldwide. Its more widespread use will lead to the

provision of therapy (see below) to uninfected patients resulting in a

maximal chance of cure.

SEVERE COMBINED IMMUNODEFICIENCY CAUSED BY A CYTOKINESIGNALING DEFICIENCY The most frequent SCID phenotype

(accounting for 30–40% of all cases) is the absence of both T and NK

cells. This outcome results from a deficiency in either the common γ

chain (γc)receptor that is shared by several cytokine receptors (the IL-2,

-4, -7, -9, -15, and -21 receptors) or Jak-associated kinase (JAK) 3 that

binds to the cytoplasmic portion of the γc chain receptor and induces

signal transduction following cytokine binding. The former form of

SCID (γc deficiency) has an X-linked inheritance mode, while the second is autosomal recessive. A lack of the IL-7Rα chain (which, together

with γc, forms the IL-7 receptor) induces a selective T-cell deficiency.

PURINE METABOLISM DEFICIENCY Ten to 20% of SCID patients

exhibit a deficiency in adenosine deaminase (ADA), an enzyme of

purine metabolism that deaminates adenosine (ado) and deoxyadenosine (dAdo). An ADA deficiency results in the accumulation of ado

and dAdo metabolites that induce premature cell death of lymphocyte

progenitors. The condition results in the absence of B and NK lymphocytes as well as T cells. The clinical expression of complete ADA

deficiency typically occurs very early in life. Since ADA is a ubiquitous

enzyme, its deficiency can also cause bone dysplasia with abnormal

costochondral junctions and metaphyses (found in 50% of cases) and

neurologic defects. The very rare purine nucleoside phosphorylase

(PNP) deficiency causes a profound although incomplete T-cell deficiency that is often associated with severe neurologic impairments.

DEFECTIVE REARRANGEMENTS OF T- AND B-CELL RECEPTORS A

series of SCID conditions are characterized by a selective deficiency in

T and B lymphocytes with autosomal recessive inheritance. These conditions account for 20–30% of SCID cases and result from mutations

in genes encoding proteins that mediate the recombination of V(D)J

gene elements in T- and B-cell antigen receptor genes (required for the

Prevention of cell apoptosis

DNA replication (purine metabolism)

ADA

γc cytokine-dependent signal

γc, JAK-3, IL7Rα

Pre TCR/TCR signalling

CD45, CD3δ, ε, ζ

V(D)J recombination

Rag-1/-2, Artemis,

DNA PKcs, DNA L4,

Cernunnos

Myeloid

compartment

Cell survival

Adenylate kinase 2

Thymus

NK

CD8

CD4

B

CLP

HSC

FIGURE 351-3 T-cell differentiation and severe combined immunodeficiencies (SCIDs). The vertical bars indicate

the five mechanisms currently known to lead to SCID. The names of deficient proteins are indicated in the boxes

adjacent to the vertical bars. A broken line means that deficiency is partial or involves only some of the indicated

immunodeficiencies. ADA, adenosine deaminase deficiency; CLPs, common lymphoid progenitors; DNAL4, DNA ligase

4; HSCs, hematopoietic stem cells; NKs, natural killer cells; TCR, T-cell receptor.

2714 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

generation of diversity in antigen recognition). The main deficiencies

involve RAG1, RAG2, DNA-dependent protein kinase, and Artemis.

A less severe (albeit variable) immunologic phenotype can result from

other deficiencies in the same pathway, that is, DNA ligase 4 and

Cernunnos deficiencies. Given that these latter factors are involved in

DNA repair, these deficiencies may also cause developmental defects.

DEFECTIVE (PRE-)T-CELL RECEPTOR SIGNALING IN THE THYMUS A

selective T-cell defect can be caused by a series of rare deficiencies in

molecules involved in signaling via the pre-TCR or the TCR. These

include deficiencies in CD3 subunits associated with the (pre-)TCR

(i.e., CD3δ, ε, and ζ) and CD45.

RETICULAR DYSGENESIS Reticular dysgenesis is an extremely rare form

of SCID that causes T and NK deficiencies with severe neutropenia and

sensorineural deafness. It results from an adenylate kinase 2 deficiency.

RAC-2 gain of function can cause the same immunologic phenotype.

Patients with SCID require appropriate care with aggressive antiinfective therapies, immunoglobulin replacement, and (when necessary) parenteral nutrition support. In most cases, curative treatment

relies on HSCT. Today, HSCT provides a very high curative potential

for SCID patients who are otherwise in reasonably good condition.

Gene therapy has been found to be successful for cases of X-linked

SCID (γc deficiency) and SCID caused by an ADA deficiency. Lastly,

a third option for the treatment of ADA deficiency consists of enzyme

substitution with a pegylated enzyme.

Thymic Defects A profound T-cell defect can also result from

faulty development of the thymus, as is most often observed in rare

cases of DiGeorge’s syndrome—a relatively common condition leading

to a constellation of developmental defects. In ~1% of such cases, the

thymus is completely absent, leading to virtually no mature T cells.

However, expansion of oligoclonal T cells can occur and is associated with skin lesions. Diagnosis (using immunofluorescence in situ

hybridization) is based on the identification of a hemizygous deletion

in the long arm of chromosome 22. To recover the capability for T-cell

differentiation, these cases require a thymic graft. CHARGE (coloboma

of the eye, heart anomaly, choanal atresia, retardation, genital, and ear

anomalies) syndrome (CHD7 deficiency) is a less frequent cause of

impaired thymus development. Lastly, the very rare “nude” defect is

characterized by the absence of both hair and the thymus.

Omenn Syndrome Omenn syndrome consists of a subset of T-cell

deficiencies that present with a unique phenotype, including earlyonset erythroderma, alopecia, hepatosplenomegaly, and failure to

thrive. These patients usually display T-cell lymphocytosis, eosinophilia, and low B-cell counts. It has been found that the T cells of these

patients exhibit a low TCR heterogeneity. This peculiar syndrome is

the consequence of hypomorphic mutations in genes usually associated with SCID, that is, RAG1, RAG2, or (less frequently) ARTEMIS or

IL-7Rα. The impaired homeostasis of differentiating T cells thus causes

this immune system–associated disease. These patients are very fragile,

requiring simultaneous anti-infective therapy, nutritional support, and

immunosuppression. HSCT provides a curative approach.

Functional T-Cell Defects (Fig. 351-2) A subset of T-cell PIDs

with autosomal inheritance is characterized by partially preserved

T-cell differentiation but defective activation resulting in abnormal

effector function. There are many causes of these defects, but all lead

to susceptibility to viral and opportunistic infections, chronic diarrhea,

and failure to thrive, with onset during childhood often associated

with autoimmune manifestations. Careful phenotyping and in vitro

functional assays are required to identify these diseases, the best characterized of which are the following.

ZETA-ASSOCIATED PROTEIN 70 (ZAP70) DEFICIENCY Zeta-associated

protein 70 (ZAP70) is recruited to the TCR following antigen recognition. A ZAP70 deficiency leads typically to an almost complete absence

of CD8+ T cells; CD4+ T cells are present but cannot be activated in

vitro by TCR stimulation.

CALCIUM SIGNALING DEFECTS A small number of patients have

been reported who exhibit a profound defect in in vitro T- and B-cell

activation as a result of defective antigen receptor-mediated Ca2+

influx. This defect is caused by a mutation in the calcium channel gene

(ORAI1) or its activator (STIM-1). It is noteworthy that these patients

are also prone to autoimmune manifestations (blood cytopenias) and

exhibit a nonprogressive muscle disease.

HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II DEFICIENCY Defective

expression of HLA class II molecules is the hallmark of a group of four

recessive genetic defects all of which affect molecules (RFX5, RFXAP,

RFXANK, and CIITA) involved in the transactivation of the genes coding for HLA class II. As a result, low but variable CD4+ T-cell counts

are observed in addition to defective antigen-specific T- and B-cell

responses. These patients are particularly susceptible to herpesvirus,

adenovirus, and enterovirus infections and chronic gut/liver Cryptosporidium infections.

HLA CLASS I DEFICIENCY Defective expression of molecules involved

in antigen presentation by HLA class I molecules (i.e., TAP-1, TAP-2,

and Tapasin) leads to reduced CD8+ T-cell counts, loss of HLA class

I antigen expression, and a particular phenotype consisting of chronic

obstructive pulmonary disease and severe vasculitis.

OTHER DEFECTS A variety of other T-cell PIDs have been described,

some of which are associated with a precise molecular defect (e.g.,

IL-2-inducible T-cell kinase [ITK] deficiency; CD27, CD70, IL-21, and

IL-21 receptor deficiencies; CARD11 deficiency; MALT1 deficiency;

BCL10 deficiency; DOCK2 deficiency; RORC deficiency; RLTPR deficiency). These conditions are also characterized by profound vulnerability to infections, such as severe Epstein-Barr virus (EBV)–induced

B-cell proliferation and autoimmune disorders. Milder phenotypes

are associated with CD8 and CD3γ deficiencies. Combined immunodeficiency associated with anhidrotic ectodermic dysplasia is the consequence of defects in the NF-κB signaling pathway (X-linked IKKγ

deficiency and gain-of-function IKbα

).

HSCT is indicated for most of these diseases, although the prognosis

is worse than in SCID because many patients are chronically infected

at the time of diagnosis. Fairly aggressive immunosuppression and

myeloablation may be necessary to achieve engraftment of allogeneic

stem cells.

T-Cell Primary Immunodeficiencies with DNA Repair

Defects This is a group of PIDs characterized by a combination of

T- and B-cell defects of variable intensity, together with a number of

nonimmunologic features resulting from DNA fragility. The autosomal

recessive disorder ataxia-telangiectasia (AT) is the most frequently

encountered condition in this group. It has an incidence of 1:40,000

live births and causes B-cell defects (low IgA, IgG2 deficiency, and low

antibody production), which often require immunoglobulin replacement. AT is associated with a progressive T-cell immunodeficiency.

As the name suggests, the hallmark features of AT are telangiectasia

and cerebellar ataxia. The latter manifestations may not be detectable

before the age of 3–4 years, so that AT should be considered in young

children with IgA deficiency and recurrent and problematic infections.

Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14)

in lymphocytes. AT is caused by a mutation in the gene encoding the

ATM protein—a kinase that plays an important role in the detection

and repair of DNA lesions (or cell death if the lesions are too numerous) by triggering several different pathways. Overall, AT is a progressive disease that carries a very high risk of lymphoma, leukemia, and

(during adulthood) carcinomas. A variant of AT (“AT-like disease”) is

caused by mutation in the MRE11 gene.

Nijmegen breakage syndrome (NBS) is a less common condition that

also results from chromosome instability (with the same cytogenetic

abnormalities as in AT). NBS is characterized by a severe T- and B-cell

combined immune deficiency with autosomal recessive inheritance.

Individuals with NBS exhibit microcephaly and a bird-like face but

have neither ataxia nor telangiectasia. The risk of malignancies is very

high. NBS results from a deficiency in nibrin (NBSI, a protein associated with MRE11 and Rad50 that is involved in checking DNA lesions)

caused by hypomorphic mutations.