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Overview of Immunodeficiency Disorders


James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Last full review/revision Apr 2021| Content last modified Apr 2021
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Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies are genetically determined and can be hereditary; secondary immunodeficiencies are acquired and much more common.

Evaluation of immunodeficiency includes history, physical examination, and immune function testing. Testing varies based on the following:

  • Whether a primary or secondary immunodeficiency is suspected

  • For primary immunodeficiency, which component of the immune system is thought to be deficient

Primary Immunodeficiencies

These disorders are genetically determined; they may occur alone or as part of a syndrome. In 2019, the International Union of Immunological Sciences reported that 354 inborn errors of immunity and 430 genes have been linked to primary immunodeficiency disorders (1).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 years 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:

As more molecular defects are defined, classifying immunodeficiencies by their molecular defects will become more appropriate (2).

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. Despite the presence of immunodeficiencies, some patients also develop autoimmune disorders.

Immunodeficiency typically manifests as recurrent infections. The age at which recurrent infections began provides a clue as to which component of the immune system is affected. Other characteristic findings tentatively suggest a clinical diagnosis (see Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders). However, tests are needed to confirm a diagnosis of immunodeficiency (see Initial and Additional Laboratory Tests for Immunodeficiency). If clinical findings or initial tests suggest a specific disorder of immune cell or complement function, additional tests are indicated (see Specific and Advanced Laboratory Tests for Immunodeficiency).

Treatment and prognosis of primary immunodeficiency disorders depend on the specific disorder (3).

Humoral immunity deficiencies

Humoral immunity deficiencies (B-cell defects) that cause antibody deficiencies account for 50 to 60% of primary immunodeficiencies (see table Humoral Immunity Deficiencies). Serum antibody titers decrease, predisposing to bacterial infections.

The most common B-cell disorder is

For diagnostic evaluation of humoral immunity deficiencies, see Approach to the Patient With Suspected Immunodeficiency and table Specific and Advanced Laboratory Tests for Immunodeficiency.


Humoral Immunity Deficiencies



Genes Affected

Clinical Findings



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

Usually diagnosed in patients aged 20–40 years

Autosomal recessive


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

No leukopenia

Autosomal recessive


Similar to X-linked hyper-IgM syndrome

Lymphoid hypoplasia, neutropenia


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


Recurrent sinopulmonary infections

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

Can occur in mild, moderate, severe, and memory phenotypes


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)


Usually asymptomatic

Sometimes recurrent sinopulmonary or GI infections, candidiasis, meningitis



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

AID= activation-dependent (induced) cytidine deaminase; BAFFR = B-cell activating factor receptor; BTK = Bruton tyrosine kinase; C = complement; CAML = calcium-modulator and cyclophilin ligand; CD = clusters of differentiation; CNS = central nervous system; CR2= complement receptor 2,;CTLA4 = cytotoxic T-lymphocyte-associated protein 4; GATA2= GATA binding protein 2; GI = gastrointestinal; ICOS = inducible T-cell co-stimulator; IL21= interleukin 21 ; JAK3= Janus kinase 3 ; NKFKB2 = nuclear factor kappa B subunit 2; PIK3CD = phosphatidyl 3-kinase catalytic subunit delta; RAG2= recombination activating 2 gene ; SLE = systemic lupus erythematosus; STAT3 = signal transducer and activator of transcription 3; TACI = transmembrane activator and CAML interactor; UNG = uracil DNA glycosylase.

Cellular immunity deficiencies

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 (see table Cellular Immunity Deficiencies). T-cell disorders also cause Ig deficiencies because the B- and T-cell immune systems are interdependent.

The most common T-cell disorders are

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.

For diagnostic evaluation of cellular immunity deficiencies, see tables Initial and Additional Laboratory Tests for Immunodeficiency and Specific and Advanced Laboratory Tests for Immunodeficiency.


Cellular Immunity Deficiencies



Gene Affected

Clinical Findings

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)

Autosomal dominant

Genes at chromosomal region 22q11.2

Genes at chromosome 10p13

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


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

Autosomal recessive


Common and opportunistic infections

No CD8 cells

AIRE = autoimmune regulator; CD = clusters of differentiation; SH2D1A = SH2 domain containing 1A; STAT = signal transducer and activator of transcription; XIAP = X-linked inhibitor of apoptosis.

Combined humoral and cellular immunity deficiencies

Combined humoral and cellular immunity deficiencies (B- and T-cell defects) account for about 20% of primary immunodeficiencies (see table Combined Humoral and Cellular Immunity Deficiencies).

The most important form is

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.

For diagnostic evaluation of combined humoral and cellular immunodeficiencies, see table Specific and Advanced Laboratory Tests for Immunodeficiency.


Combined Humoral and Cellular Immunity Deficiencies



Gene Affected

Clinical Findings

Autosomal recessive


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 immunoglobulins

Autosomal recessive or X-linked


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

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

Various including, RFX: RFXANK, RFX5, and RFXAP

Common and opportunistic infections

Autosomal recessive or X-linked

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


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

X-linked recessive


Typically, pyogenic and opportunistic infections, eczema, thrombocytopenia

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

* Omenn syndrome is an autosomal recessive form of severe SCID causing erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, eosinophilia, hepatosplenomegaly, and elevated serum IgE levels.

ADA = adenosine deaminase; ATM = ataxia telangiectasia–mutated; DOCK = dedicator of cytokinesis; IL-2RG = IL-2 receptor gamma; JAK = Janus kinase; MHC = major histocompatibility complex; NEMO = nuclear factor–kappa-B essential modulator; PTPRC = protein tyrosine phosphatase, receptor type, C; RAG = recombination activating gene; RFX = regulatory factor X; RFXANK= RFX containing ankyrin repeats; RFXAP = RFX-associated protein; RMRP = ribonuclease mitochondrial RNA-processing; SCID = severe combined immunodeficiency; STAT = signal transducer and activator of transcription; TYK = tyrosine kinase; WASP = Wiskott-Aldrich syndrome protein.

Phagocytic cell defects

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 (see table Phagocytic Cell Defects). Cutaneous staphylococcal and gram-negative infections are characteristic.

The most common (although still rare) phagocytic cell defects are


Phagocytic Cell Defects



Genes Affected

Clinical Findings

Autosomal recessive


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

X-linked or autosomal recessive

gp91phox (CYBB; X-linked)

p22phox, p47phox, p67phox (autosomal recessive)

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

Autosomal recessive

ITGB2 gene, encoding CD18 of beta-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-gamma receptor, IL-12, or the IL-12 receptor

Mycobacterial infections

Varying clinical severity based on genetic defect

Cyclic neutropenia

Autosomal dominant


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

CD = clusters of differentiation; CHS = Chédiak-Higashi syndrome; CYBB = cytochrome b-245, beta polypeptide; ELA = elastase; GDP = glucose diphosphate; gp = glycoprotein; IFN = interferon; IL = interleukin; ITGB2 = integrin beta-2; LYST = lysosomal transporter.

Complement deficiencies

Complement deficiencies are rare ( 2%); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired (see table Complement Deficiencies). 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

  • Autoimmune disorders (eg, systemic lupus erythematosus, glomerulonephritis), which are due to defective clearance of antigen-antibody complexes

A deficiency in a complement regulatory protein causes hereditary angioedema.

Complement deficiencies can affect the classical and/or alternate pathways of the 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.


Complement Deficiencies



Clinical Findings


Autosomal recessive



Autosomal recessive

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


Autosomal recessive

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


Autosomal recessive

SLE, other autoimmune disorders (eg, IgA nephropathy, progressive systemic sclerosis, IgA-associated vasculitis, 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


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



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


Pyogenic infections



Increased risk of fulminant neisserial infection

Complement regulatory protein deficiencies

C1 inhibitor

Autosomal dominant

Factor I

Autosomal codominant

Same as C3 deficiency

Factor H

Autosomal codominant

Same as C3 deficiency

Decay accelerating factor

Autosomal recessive

Complement receptor (CR) deficiencies



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


Autosomal recessive

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

C = complement; MASP = mannose-binding lectin-associated serine protease; MBL = mannose-binding lectin; SLE = systemic lupus erythematosus.

Primary immunodeficiency references

  • 1. Tangye SG, Al-Herz W, Bousfiha A, et al: Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 40(1):24–64, 2020. doi: 10.1007/s10875-019-00737-x

  • 2. Chinn IK, Chan AY, Chen K, et al: Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 145(1):46–69, 2020. doi: 10.1016/j.jaci.2019.09.009

  • 3. Leonardi L, Rivalta B, Cancrini C, et al: Update in primary immunodeficiencies. Acta Biomed 91(11-S):e2020010, 2020. doi: 10.23750/abm.v91i11-S.10314

Secondary Immunodeficiencies

Causes (see table Causes of Secondary Immunodeficiency) include

  • 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







Certain drugs, such as chemotherapeutic drugs, immunosuppressants, corticosteroids; radiation therapy; splenectomy


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



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


Nephrotic syndrome, renal insufficiency, uremia



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


Some Drugs That Cause Immunosuppression



Antiseizure drugs

Lamotrigine, phenytoin, valproate

Disease-modifying anti-rheumatic drugs (DMARDs)

Interleukin (IL)-1 inhibitors (eg, anakinra)

IL-6 inhibitors (eg, tocilizumab)

IL-17 inhibitors (eg, brodalumab)

Tumor necrosis factor (TNF) inhibitors (eg, adalimumab, etanercept, infliximab)

T-cell activation inhibitors (eg, abatacept, basiliximab)

CD20 inhibitors (eg, rituximab)

CD3 inhibitors (eg, muromonab-CD3)

Janus kinase (JAK) inhibitors (eg, ruxolitinib)

Calcineurin inhibitors

Cyclosporine, tacrolimus


Methylprednisolone, prednisone

Cytotoxic chemotherapy drugs

Purine metabolism inhibitors

Azathioprine, mycophenolate mofetil


Everolimus, sirolimus

Immunosuppressive immunoglobulins

Antilymphocyte globulin, antithymocyte globulin

Immunodeficiency can result from loss of serum proteins (particularly IgG and albumin) through the following:

  • The kidneys in nephrotic syndrome

  • The skin in severe burns or dermatitis

  • The gastrointestinal (GI) tract in enteropathy

Enteropathy may also lead to lymphocyte loss, resulting in lymphopenia.

Treatment focuses on the underlying disorder; for example, a diet high in medium-chain triglycerides may decrease loss of immunoglobulins (Igs) and lymphocytes from the gastrointestinal tract and be remarkably beneficial.

If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder (eg, diabetes, HIV infection, cystic fibrosis, primary ciliary dyskinesia).

Geriatrics Essentials

Some decrease in immunity occurs with aging. For example, in older adults, the thymus tends to produce fewer naive T cells; thus, fewer T cells are available to respond to new antigens. The total 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 older adults, impairs immune responses. Calcium, zinc, and vitamin E are particularly important to immunity. Risk of calcium deficiency is increased in older adults, partly because with aging, the intestine becomes less able to absorb calcium. Also, the elderly may not ingest enough calcium in their diet. Zinc deficiency is very common among adults living in institutional settings and homebound patients.

Certain disorders (eg, diabetes, chronic kidney disease, undernutrition), which are more common among older adults, 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 (genetic) 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 older adults.

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