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Overview of Immunodeficiency Disorders

by James Fernandez, MD, PhD

Immunodeficiency disorders are associated with or predispose affected patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies are hereditary; secondary immunodeficiencies are acquired. Secondary immunodeficiencies are much more common.

Secondary immunodeficiencies

  • Systemic disorders (eg, diabetes, undernutrition, HIV infection)

  • Immunosuppressive treatments (eg, cytotoxic chemotherapy, bone marrow ablation before transplantation, radiation therapy)

  • Prolonged serious illness

Secondary immunodeficiency also occurs among critically ill, older, or hospitalized patients. Prolonged serious illness may impair immune responses; impairment is often reversible if the underlying illness resolves.

Causes of Secondary Immunodeficiency

Category

Examples

Endocrine

Diabetes mellitus

GI

Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy

Hematologic

Aplastic anemia, cancers (eg, chronic lymphocytic leukemia, multiple myeloma, Hodgkin lymphoma), graft-vs-host disease, sickle cell disease, splenectomy

Iatrogenic

Certain drugs, such as chemotherapeutic drugs, immunosuppressants, corticosteroids ( Some Drugs That Cause Immunosuppression); radiation therapy; splenectomy

Infectious

Viral infections (eg, cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus), bacterial infections, rare bacterial infections with superantigens (antigens that can activate large numbers of T cells, resulting in massive cytokine production, most notably from Staphylococcus aureus), mycobacterial infections

Nutritional

Alcoholism, undernutrition

Physiologic

Physiologic immunodeficiency in infants due to immaturity of the immune system, pregnancy

Renal

Nephrotic syndrome, renal insufficiency, uremia

Rheumatologic

RA, SLE

Other

Burns, cancers, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis

Some Drugs That Cause Immunosuppression

Class

Examples

Anticonvulsants

Carbamazepine, diphenylhydantoin, lamotrigine, phenytoin, valproate

Disease-modifying anti-rheumatic drugs (DMARDs)

Abatacept, anakinra, d -penicillamine, etanercept

Calcineurin inhibitors

Cyclosporine, tacrolimus

Corticosteroids

Methylprednisolone, prednisone

Cytotoxic chemotherapy drugs

Purine metabolism inhibitors

Azathioprine, mycophenolate mofetil

Rapamycins

Everolimus, sirolimus

Immunosuppressive immunoglobulins

Antilymphocyte globulin, antithymocyte globulin

Monoclonal antibodies

Adalimumab, basiliximab, daclizumab, infliximab, OKT3, rituximab, tocilizumab

Immunodeficiency can result from loss of serum proteins (particularly IgG and albumin) through the kidneys in nephrotic syndrome, through skin in severe burns or dermatitis, or through the GI tract in enteropathy. Enteropathy may also lead to lymphocyte loss, resulting in lymphopenia. These disorders can mimic B- and T-cell defects. Treatment focuses on the underlying disorder; a diet high in medium-chain triglycerides may decrease loss of Igs and lymphocytes from the GI tract and be remarkably beneficial.

Primary immunodeficiencies

These disorders are genetically determined; they may occur alone or as part of a syndrome. More than 100 of these disorders have been described, and heterogeneity within each disorder may be considerable. The molecular basis for about 80% is known. Primary immunodeficiencies typically manifest during infancy and childhood as abnormally frequent (recurrent) or unusual infections. About 70% of patients are < 20 yr at onset; because transmission is often X-linked, 60% are male. Overall incidence of symptomatic disease is about 1/280 people.

Primary immunodeficiencies are classified by the main component of the immune system that is deficient, absent, or defective ( Primary Immunodeficiency Disorders):

  • Humoral immunity

  • Cellular immunity

  • Combined humoral and cellular immunity

  • Phagocytic cells

  • Complement proteins

As more molecular defects are defined, classifying immunodeficiencies by their molecular defects will become more appropriate.

Humoral immunity deficiencies (B-cell defects) that cause Ig and antibody deficiencies account for 50 to 60% of primary immunodeficiencies. Serum Ig and antibody titers decrease, predisposing to bacterial infections. The most common B-cell disorder is selective IgA deficiency.

Cellular immunity deficiencies (T-cell defects) account for about 5 to 10% of primary immunodeficiencies and predispose to infection by viruses, Pneumocystis jirovecii, fungi, other opportunistic organisms, and many common pathogens. T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent. The most common T-cell disorders are DiGeorge syndrome, ZAP-70 deficiency, X-linked lymphoproliferative syndrome, and chronic mucocutaneous candidiasis (see Chronic Mucocutaneous Candidiasis). Primary natural killer cell defects, which are very rare, may predispose to viral infections and tumors. Secondary natural killer cell defects can occur in patients who have various other primary or secondary immunodeficiencies.

Combined humoral and cellular immunity deficiencies (B- and T-cell defects) account for about 20% of primary immunodeficiencies. The most important form is severe combined immunodeficiency (SCID). In some forms of combined immunodeficiency (eg, purine nucleoside phosphorylase deficiency), Ig levels are normal or elevated, but because of inadequate T-cell function, antibody formation is impaired.

Phagocytic cell defects account for 10 to 15% of primary immunodeficiencies; the ability of phagocytic cells (eg, monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens is impaired. Cutaneous staphylococcal and gram-negative infections are characteristic. The most common phagocytic cell defects are chronic granulomatous disease, leukocyte adhesion deficiency (types 1 and 2), cyclic neutropenia, and Chédiak-Higashi syndrome.

Complement deficiencies are rare ( 2%); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired. Hereditary deficiencies are autosomal recessive except for deficiencies of C1 inhibitor, which is autosomal dominant, and properdin, which is X-linked. The deficiencies result in defective opsonization, phagocytosis, and lysis of pathogens and in defective clearance of antigen-antibody complexes. The most serious consequences are recurrent infection, which is due to defective opsonization, and autoimmune disorders (eg, SLE, glomerulonephritis), which is due to defective clearance of antigen-antibody complexes (see Primary Immunodeficiency Disorders). A deficiency in a complement regulatory protein causes hereditary angioedema. Complement deficiencies can affect the classical and/or alternate pathways (see see Complement System). The alternate pathway shares C3 and C5 through C9 with the classical pathway but has additional components: factor D, factor B, properdin (P), and regulatory factors H and I.

Primary Immunodeficiency Disorders

Disorder

Inheritance

Gene Affected

Clinical Findings

Humoral immunity deficiencies

Common variable immunodeficiency

Variable

TACI , ICOS , BAFFR

Recurrent sinopulmonary infections, autoimmune disorders (eg, immune thrombocytopenia, autoimmune hemolytic anemia), malabsorption, granulomatous interstitial lung disease, nodular lymphoid hyperplasia of GI tract, bronchiectasis, lymphoid interstitial pneumonia, splenomegaly; in 10%, gastric carcinoma and lymphoma

Usually diagnosed in patients aged 20–40 yr

Hyper-IgM syndrome with AID or UNG deficiencies

Autosomal recessive

AID , UNG

Similar to X-linked hyper-IgM syndrome but with lymphoid hyperplasia

No leukopenia

Hyper-IgM syndrome with CD40 deficiency

Autosomal recessive

CD40

Similar to X-linked hyper-IgM syndrome

Lymphoid hypoplasia, neutropenia

Hyper-IgM syndrome with CD40 ligand deficiency

X-linked

CD40 ligand (CD40L)

Similar to X-linked agammaglobulinemia (eg, recurrent pyogenic bacterial sinopulmonary infections) but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia

Selective antibody deficiency with normal immunoglobulins

Unknown

Recurrent sinopulmonary infections

Sometimes atopic manifestations (eg, atopic dermatitis, asthma, chronic rhinitis)

Selective IgA deficiency

Unknown

In some cases, TACI

Most often asymptomatic

Recurrent sinopulmonary infections, diarrhea, allergies (including anaphylactic transfusion reactions [rare]), autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis)

Transient hypogammaglobulinemia of infancy

Unknown

Usually asymptomatic

Sometimes recurrent sinopulmonary or GI infections, candidiasis, meningitis

X-linked agammaglobulinemia

X-linked

BTK

Recurrent sinopulmonary and skin infections during infancy, transient neutropenia, lymphoid hypoplasia

Persistent CNS infections resulting from live-attenuated oral polio vaccine, echoviruses, or coxsackieviruses

Increased risk of infectious arthritis, bronchiectasis, and certain cancers

Cellular immunity deficiencies

Chronic mucocutaneous candidiasis

Autosomal dominant or recessive

STAT1 (dominant)

AIRE (recessive)

Persistent or recurrent candidal infections, onychomycosis, autosomal recessive autoimmune polyendocrinopathy–candidosis-ectodermal dystrophy (with hypoparathyroidism and adrenal insufficiency)

DiGeorge syndrome

Autosomal

Genes at chromosomal region 22q11.2,

Genes at chromosome 10p13

Unusual facies with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections, developmental delay

X-linked lymphoproliferative syndrome

X-linked

SH2D1A (type 1)

XIAP (type 2)

Asymptomatic until onset of Epstein-Barr virus infection, then fulminant or fatal infectious mononucleosis with liver failure, B-cell lymphomas, splenomegaly, aplastic anemia

ζ-Associated protein 70 (ZAP-70) deficiency

Autosomal recessive

Common and opportunistic infections

No CD8 cells

Combined humoral and cellular immunity deficiencies

Ataxia-telangiectasia

Autosomal recessive

ATM

Ataxia, telangiectasias, recurrent sinopulmonary infections, endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus), increased risk of cancer

Cartilage-hair hypoplasia

Autosomal recessive

Short-limbed dwarfism, common and opportunistic infections

Combined immunodeficiency with inadequate but not absent T-cell function and normal or elevated Igs

Autosomal recessive or X-linked

NEMO

Common and opportunistic infections, lymphopenia, lymphadenopathy, hepatosplenomegaly, skin lesions resembling those of Langerhans cell histiocytosis in some patients

Hyper-IgE syndrome

Autosomal dominant or recessive

STAT3 (dominant)

TYK2 , DOCK8 (recessive)

Sinopulmonary infections; staphylococcal abscesses of skin, lungs, joints, and viscera; pulmonary pneumatoceles; pruritic dermatitis; coarse facial features; delayed shedding of baby teeth; osteopenia; recurrent fractures; tissue and blood eosinophilia

MHC antigen deficiencies

Autosomal recessive

Common and opportunistic infections

Severe combined immunodeficiency

Autosomal recessive or X-linked

JAK3 , PTPRC [ CD45] , RAG1 , RAG2 (autosomal recessive)

IL-2RG (X-linked)

Oral candidiasis, P. jirovecii pneumonia, diarrhea before 6 mo, failure to thrive, graft vs host disease, absent thymic shadow, lymphopenia, bone abnormalities (in ADA deficiency), exfoliative dermatitis as part of Omenn syndrome

Wiskott-Aldrich syndrome

X-linked recessive

WASP

Typically, pyogenic and opportunistic infections, eczema, thrombocytopenia

Possibly GI bleeding (eg, bloody diarrhea), recurrent respiratory infections, cancer (in 10% of patients > 10 yr), varicella-zoster virus infection, herpesvirus infection

Phagocytic cell defects

Chédiak-Higashi syndrome

Autosomal recessive

LYST [CHS1]

Oculocutaneous albinism, recurrent infections, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neurologic changes, pancytopenia, bleeding diathesis

Chronic granulomatous disease

X-linked or autosomal recessive

GP91PHOX ( CYBB ; X-linked)

p22phox, p47phox, p67phox (autosomal recessive)

Granulomatous lesions in the lungs, liver, lymph nodes, and GI and GU tract (causing obstruction); lymphadenitis; hepatosplenomegaly; skin, lymph node, lung, liver, and perianal abscesses; osteomyelitis; pneumonia; staphylococcal, gram-negative, and aspergillus infections

Leukocyte adhesion deficiency

Autosomal recessive

I ITGB2 gene, encoding CD18 of β 2 integrins (type 1)

GDP-fucose transporter gene (type 2)

Soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis, no formation of pus

Developmental delay (type 2).

Mendelian susceptibility to mycobacterial disease (MSMD)

Autosomal dominant or recessive

Defects in genes encoding the IFN-γ receptor, IL-12, or the IL-12 receptor

Mycobacterial infections

Cyclic neutropenia

Autosomal dominant

ELA2

Pyogenic bacterial infections during recurrent episodes of neutropenia (eg, every 14 to 35 days)

Complement deficiencies in the classical pathway

C1

Autosomal recessive

SLE

C2

Autosomal recessive

SLE, recurrent pyogenic infections with encapsulated bacteria (especially pneumococcal) that start in early childhood, other autoimmune disorders (eg, glomerulonephritis, polymyositis, vasculitis, Henoch-Schönlein purpura, Hodgkin lymphoma)

C3

Autosomal recessive

Recurrent pyogenic infections with encapsulated bacteria that start at birth, glomerulonephritis, other antigen-antibody complex disorders, sepsis

C4

Autosomal recessive

SLE, other autoimmune disorders (eg, IgA nephropathy, progressive systemic sclerosis, Henoch-Schönlein purpura, type 1 diabetes mellitus, autoimmune hepatitis)

C5, C6, C7, C8, C9 (membrane attack complex)

Autosomal recessive

Recurrent Neisseria meningitidis and disseminated N. gonorrhoeae infections

Complement deficiencies in the MBL pathway

MBL

Autosomal recessive

Recurrent pyogenic infections with encapsulated bacteria that start at birth; unexplained sepsis; increased severity of infection in secondary immunodeficiencies due to corticosteroid use, cystic fibrosis, or chronic lung disorders

MASP-2

Unknown

Autoimmune disorders (eg, inflammatory bowel disease, erythema multiforme), recurrent pyogenic infections with encapsulated bacteria (eg, Streptococcus pneumoniae)

Complement deficiencies in the alternative pathway

Factor B

Autosomal recessive

Pyogenic infections

Factor D

Autosomal

Pyogenic infections

Properdin

X-linked

Increased risk of fulminant neisserial infection

Complement regulatory protein deficiencies

C1 inhibitor

Autosomal dominant

Angioedema

Factor I

Autosomal codominant

Same as C3 deficiency

Factor H

Autosomal codominant

Same as C3 deficiency

Hemolytic-uremic syndrome

Decay accelerating factor

Autosomal recessive

Paroxysmal nocturnal hemoglobinuria

Complement receptor (CR) deficiencies

CR1

Acquired

Secondary finding in immune (antigen-antibody) complex–mediated disease

CR3

Autosomal recessive

Leukocyte adhesion deficiency syndrome (recurrent Staphylococcus aureus and Pseudomonas aeruginosa infections)

ADA = adenosine deaminase; AID = activation-dependent (induced) cytidine deaminase; AIRE = autoimmune regulator; ATM = ataxia telangiectasia–mutated; BAFFR ; B-cell activating factor receptor; BTK = Bruton tyrosine kinase; C = complement; CAML = calcium-modulator and cyclophilin ligand; CD = clusters of differentiation; CYBB = cytochrome b-245, beta polypeptide; DOCK = dedicator of cytokinesis; ELA = elastase; GDP = glucose diphosphate; ICOS = inducible T-cell co-stimulator; IFN = interferon; IL-2RG = IL-2 receptor γ; ITGB2 = integrin β 2 ; JAK = Janus kinase; LYST = lysosomal transporter; MASP = mannose-binding lectin-associated serine protease; MBL = mannose-binding lectin; MHC = major histocompatibility complex; NEMO = nuclear factor–kappa-B essential modulator; PTPRC = protein tyrosine phosphatase, receptor type, C; RAG = recombination activating gene; SH2D1A = SH2 domain containing 1A; STAT = signal transducer and activator of transcription; TACI = transmembrane activator and CAML interactor; TYK = tyrosine kinase; UNG = uracil DNA glycosylase; WASP = Wiskott-Aldrich syndrome protein; XIAP = X-linked inhibitor of apoptosis.

Primary immunodeficiency syndromes are genetically determined immunodeficiencies with immune and nonimmune defects. Nonimmune manifestations are often more easily recognized than those of the immunodeficiency. Examples are ataxia-telangiectasia, cartilage-hair hypoplasia, DiGeorge syndrome, hyper-IgE syndrome, and Wiskott-Aldrich syndrome.

Geriatrics Essentials

Some decrease in immunity occurs with aging. For example, in the elderly, the thymus tends to produce fewer naive T cells; thus, fewer T cells are available to respond to new antigens. The number of T cells does not decrease (because of oligoclonality), but these cells can recognize only a limited number of antigens.

Signal transduction (transmission of antigen-binding signal across the cell membrane into the cell) is impaired, making T cells less likely to respond to antigens. Also, helper T cells may be less likely to signal B cells to produce antibodies.

The number of neutrophils does not decrease, but these cells become less effective in phagocytosis and microbicidal action.

Undernutrition, common among the elderly, impairs immune responses. Ca, zinc, and vitamin E are particularly important to immunity. Risk of Ca deficiency is increased in the elderly, partly because with aging, the intestine becomes less able to absorb Ca. Also, the elderly may not ingest enough Ca in their diet. Zinc deficiency is very common among the institutionalized elderly and homebound patients.

Certain disorders (eg, diabetes, chronic kidney disease, undernutrition), which are more common among the elderly, and certain therapies (eg, immunosuppressants, immunomodulatory drugs and treatments), which the elderly are more likely to use, can also impair immunity.

Key Points

  • Secondary (acquired) immunodeficiencies are much more common than primary (hereditary) immunodeficiencies.

  • Primary immunodeficiencies can affect humoral immunity (most commonly), cellular immunity, both humoral and cellular immunity, phagocytic cells, or the complement system.

  • Patients who have primary immunodeficiencies may have nonimmune manifestations that can be recognized more easily than the immunodeficiencies.

  • Immunity tends to decrease with aging partly because of age-related changes; also, conditions that impair immunity (eg, certain disorders, use of certain drugs) are more common among the elderly.

Resources In This Article

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