Immunodeficiency Disorders

Definition/Classification

Impaired defense → ↑infection + ↑cancer susceptibility.

Primary — inherited, immune system development defect. Secondary — acquired, due to other disease (infection, malnutrition, aging, immunosuppression, autoimmunity, chemo).

Primary subtypes: specific immunity (humoral/cellular/combined) vs nonspecific (complement/phagocyte/NK). Overlap common — T cell defects usually impair antibody too.

Infection pattern:

• Humoral/complement/phagocyte defect → recurrent PYOGENIC bacteria
• CMI defect → viral, fungal, intracellular bacteria

Onset: most primary immunodeficiencies present 6mo-2yr age.

Humoral (B cell) Defects

Bruton disease (X-linked agammaglobulinemia): Absent Bruton’s tyrosine kinase → pre-B cells can’t mature. Total absence of B cells/plasma cells, ↓all Ig classes. Pre-B cells normal in marrow. T cell function NORMAL. X-linked → males. Infections from 6mo (maternal Ab wanes): H. influenzae/S. pneumoniae/S. aureus (pharyngitis, sinusitis, otitis, bronchitis, pneumonia), enteroviruses, Giardia. Autoimmune disease in 20%.

Common Variable Immunodeficiency (CVID): heterogeneous. Both sexes, onset 2nd-3rd decade (LATER than Bruton). B cells PRESENT normal numbers but fail to differentiate to plasma cells. Diagnosis of exclusion. Cause variable: intrinsic B defect / deficient TH help / excess T-suppressor.

Isolated IgA deficiency: COMMONEST primary immunodeficiency (1:700). ↓mucosal defense → recurrent sinopulmonary infection + diarrhea. Linked to autoimmune disease (unexplained). Cause: block in IgA B cell→plasma cell differentiation (altered TH cytokines TGF-β/IL-5, or intrinsic defect). Other Ig normal/elevated.

Hyper-IgM syndrome: X-linked, defect in CD40L or CD40 (blocks class switchover). IgM normal/high, IgG/IgA/IgE absent. ↓IgG → ↓opsonization/complement (pyogenic infection). ↓IgA → sinopulmonary/diarrhea. Excess IgM → autoimmune hemolytic anemia/thrombocytopenia/neutropenia. CD40L needed for macrophage activation too → prone to Pneumocystis jirovecii. 70% X-linked.

Cellular (T cell) Defects

DiGeorge syndrome (thymic aplasia): congenital thymic development defect. Vulnerable to viral/fungal/intracellular bacterial/protozoal infection. 90% = chromosome 22q11 deletion → 3rd+4th pharyngeal pouch malformation → thymus + parathyroid + face/aortic arch defects. Features: parathyroid hypoplasia (neonatal tetany/hypocalcemia), cardiac anomalies (Tetralogy of Fallot), characteristic face. B cells/Ig NORMAL. Treatment: thymus transplant; partial defects may improve with age.

Chronic mucocutaneous candidiasis: impaired CMI vs Candida albicans only. Superficial skin/mucosa/nail infection. NOT ↑other infections. Associated: endocrinopathies, autoimmune disease. Rx: transfer factor + amphotericin B.

PNP (Purine nucleoside phosphorylase) deficiency: rare AR, chromosome 14. ↓purine degradation → ↑deoxyguanosine triphosphate → toxic to T cells (NOT B cells).

Combined (B+T) Defects

SCID: defects in BOTH humoral and CMI.

• 50-60% X-linked: common γ chain mutation (shared by IL-2/4/7/9/15 receptors). ↓IL-7 signaling → ↓B/T precursor survival. ↓IL-15 signaling → NK deficiency.
• AR causes:
  • ADA deficiency (COMMONEST AR SCID) — ↓purine degradation → ↑deoxyadenosine → toxic to dividing immature T cells (B cells spared)
  • RAG mutation — blocks TCR/Ig gene rearrangement → blocks T+B development
  • Jak3 mutation — blocks common γ chain signal transduction
  • Class II MHC deficiency (Bare lymphocyte syndrome) — prevents CD4+ T cell development

Infections: wide range (Candida, Pneumocystis, CMV, Pseudomonas) regardless of specific defect. Treatment: Bone marrow transplant (mainstay). Gene therapy successful in X-linked cases.

Wiskott-Aldrich Syndrome (WAS): X-linked recessive. Triad: immunodeficiency + thrombocytopenia + eczema. Severity ↑ with age. Early: ↓response to bacterial polysaccharide, ↓IgM, normal IgG, ↑IgA/IgE (paradox). Later: recurrent bacterial infection, progressive humoral+cellular loss. Prone to non-Hodgkin B cell lymphoma. Bloody diarrhea (2° thrombocytopenia). Defect: WASP gene (cytoskeletal glycoprotein, CD43/sialophorin) — needed for actin polymerization.

Ataxia telangiectasia: cerebellar ataxia + telangiectasia (eye/skin) + choreoathetoid movements (infancy) + ↓IgA (±IgE) + profound sinopulmonary infection. Defect: cell-cycle kinase mutation. Link to immune defect unclear.

Nezelof syndrome: AR, cellular immunodeficiency, thymic hypoplasia. Chronic diarrhea, viral/fungal infections, failure to thrive.

Disorders of Phagocytosis

Chronic Granulomatous Disease (CGD): NADPH oxidase defect → ↓oxidative burst → ↓microbial killing. Infections: CATALASE-POSITIVE organisms (staph, Pseudomonas, coliforms) — catalase-negative (strep, pneumococcus) handled fine. X-linked (70%, membrane component defective) vs AR (cytoplasmic component defective). Features: gingivitis, lymphadenopathy, nonmalignant granulomas. Test: NBT (Nitroblue tetrazolium) reduction test.

Myeloperoxidase deficiency: common genetic disorder, ↓quantity/function. Recurrent infection esp. Candida albicans.

Chediak-Higashi syndrome: AR. Defective phagosome-lysosome fusion (LYST mutation, regulates lysosomal trafficking). Features: recurrent severe pyogenic infection + albinism (melanocyte) + neuro abnormalities + bleeding (platelet) + aggressive nonmalignant lymphoid infiltration. Giant granules in phagocytes, can’t kill bacteria.

Leukocyte Adhesion Deficiency (LAD): rare AR. β2 integrin (CD18) or fucosyltransferase mutation → ↓leukocyte (esp neutrophil) chemotaxis. → bacterial + fungal infections.

Lazy leukocyte syndrome: idiopathic, neutrophil chemotaxis defect. Gingivitis, abscess, pneumonia, neutropenia.

Job’s syndrome (Hyper-IgE syndrome): STAT3 or DOCK8 mutation → ↓neutrophil chemotaxis. Features: eczema, recurrent staph skin abscess, recurrent lung infection (pneumatocele), eosinophilia, high serum IgE.

Complement deficiencies — see Complement System topic.

Secondary Immunodeficiencies

More common than primary overall. Causes: malnutrition, aging, infections depleting lymphocytes (HIV/AIDS — most important), bone marrow/blood cancers (leukemia, lymphoma, myeloma), proteinuric renal disease (Ig lost in urine), sarcoidosis, immunosuppressive drugs, chemo/radiotherapy.

Definition and Classification

Immunodeficiency is a state where the body’s defence mechanisms are impaired, raising susceptibility to microbial infection and certain cancers. It divides into primary (inherited defects in immune system development) and secondary (acquired, secondary to another disease process — infection, malnutrition, ageing, immunosuppression, autoimmunity, chemotherapy).

Primary immunodeficiencies are further split by which arm is defective — specific immunity (humoral, cellular, or both) or nonspecific host defence (complement, phagocytes, NK cells) — though the split is often blurry in practice, since T cell defects nearly always impair antibody synthesis too, making isolated T cell deficiency clinically indistinguishable from combined T-and-B deficiency.

The pattern of infection reliably points to which arm is affected: defects in humoral immunity, complement, or phagocytosis predispose to recurrent pyogenic bacterial infections; defects in cell-mediated immunity predispose to viral, fungal, and intracellular bacterial infections. Most primary immunodeficiencies present early — between 6 months and 2 years — because that’s when susceptibility to recurrent infection first becomes obvious.

Humoral Immunodeficiency (B Cell Defects)

Bruton disease (X-linked agammaglobulinemia) — one of the commoner primary immunodeficiencies. Absence of Bruton’s tyrosine kinase blocks pre-B cells from maturing into immature B cells, so there is total absence of circulating B cells and plasma cells and depressed levels of every immunoglobulin class, while pre-B cells remain normal in the bone marrow and T cell function is entirely normal. Because the defect is X-linked, it affects males almost exclusively. Infections begin around 6 months of age (once maternal antibody wanes) — recurrent pyogenic infections (H. influenzae, S. pneumoniae, S. aureus) causing pharyngitis, sinusitis, otitis media, bronchitis, pneumonia; enteroviral infections (normally cleared by neutralizing antibody); and giardiasis (normally resisted by secretory IgA). Autoimmune disease (SLE, dermatomyositis) occurs in up to 20%.

Common variable immunodeficiency (CVID) — a heterogeneous sporadic/inherited group with hypogammaglobulinemia, infection susceptibility, autoimmune disease, and lymphoid tumours. It differs from Bruton disease in affecting both sexes equally, presenting much later (2nd–3rd decade), and involving B cells that are present in normal numbers but fail to differentiate into plasma cells — a diagnosis of exclusion, since the precise defect (intrinsic B cell fault, deficient TH help, or excess T-suppressor activity) varies by patient.

Isolated IgA deficiency — the single commonest primary immunodeficiency (~1 in 700). Since IgA normally dominates mucosal secretions, its absence weakens intestinal and respiratory mucosal defence, causing recurrent sinopulmonary infection and diarrhoea, with an unexplained but real link to autoimmune disease. It arises from a block in terminal differentiation of IgA-secreting B cells to plasma cells (altered TH cytokine production — TGF-β, IL-5 — or an intrinsic B cell defect); other immunoglobulin classes stay normal or even elevated.

Hyper-IgM syndrome — an X-linked defect in isotype class switchover, from mutations in CD40L or CD40 that prevent the T-B cell interaction needed to switch classes. IgM stays normal-to-elevated while IgG, IgA, and IgE are essentially absent. This produces a mixed picture: IgG deficiency impairs opsonization and complement activation (recurrent pyogenic infection), IgA deficiency causes sinopulmonary infection and diarrhoea, and excess IgM can itself cause autoimmune hemolytic anaemia, thrombocytopenia, or neutropenia by reacting with blood cells. Because CD40L signalling is also needed for macrophage activation (the DTH pathway), these patients are specifically prone to Pneumocystis jirovecii. 70% of cases are X-linked.

Cellular Immunodeficiency (T Cell Defects)

DiGeorge syndrome (thymic aplasia) — a congenital defect in thymic development blocking T cell maturation, leaving infants extremely vulnerable to viral, fungal, intracellular bacterial, and protozoal infection. In 90% of cases a chromosome 22q11 deletion disrupts the third and fourth pharyngeal pouches, so the defect extends beyond the thymus to parathyroid hypoplasia (neonatal tetany, hypocalcaemia), cardiac/great-vessel anomalies (tetralogy of Fallot), and a characteristic facial appearance. B cells and immunoglobulin levels are normal. Thymic transplant restores function; partial defects can improve spontaneously with age.

Chronic mucocutaneous candidiasis — impaired CMI specifically against Candida albicans, producing superficial skin/mucosa/nail infection without broader infection susceptibility, but associated with endocrinopathies and autoimmune disease. Transfer factor therapy plus amphotericin B has been reported effective.

Purine nucleoside phosphorylase (PNP) deficiency — rare autosomal recessive disorder; PNP degrades purines, and its absence lets deoxyguanosine triphosphate accumulate to toxic levels specifically in T cells (B cells are spared), predisposing to infection and autoimmune disease.

Combined Immunodeficiencies (B and T Cell Defects)

Severe combined immunodeficiency (SCID) — a genetically diverse group unified by defects in both humoral and cell-mediated immunity. About 50–60% are X-linked, from mutations in the common γ chain shared by cytokine receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 — defective IL-7 signalling blocks survival/expansion of immature B and T precursors, and defective IL-15 signalling causes NK cell deficiency. The remaining autosomal recessive causes include: ADA (adenosine deaminase) deficiency (commonest autosomal recessive SCID — accumulated deoxyadenosine is toxic to dividing immature T cells, sparing B cells); RAG mutation (blocks the somatic gene rearrangement both T and B cell receptors need); Jak3 mutation (blocks signal transduction through the same common γ chain, a different route to the same functional defect); and Class II MHC deficiency (bare lymphocyte syndrome) (prevents CD4+ T cell development entirely). Regardless of the specific genetic lesion, affected infants suffer severe recurrent infection with a wide pathogen range (Candida, Pneumocystis, CMV, Pseudomonas). Bone marrow transplant is the mainstay of treatment; gene therapy has succeeded specifically in X-linked cases.

Wiskott–Aldrich syndrome (WAS) — X-linked recessive, with immunodeficiency, thrombocytopenia, and eczema, worsening with age. Early on: defective response to bacterial polysaccharide, low IgM, normal IgG, paradoxically elevated IgA and IgE. Other T and B responses start normal but deteriorate with age into recurrent bacterial infection and progressive loss of both humoral and cellular function; patients are prone to non-Hodgkin B cell lymphoma and may present with bloody diarrhoea from thrombocytopenia. The defect is in WASP, a cytoskeletal glycoprotein (CD43/sialophorin) required for actin polymerization in bone-marrow lymphoid precursors.

Ataxia telangiectasia — cerebellar ataxia, ocular/skin telangiectasia and choreoathetoid movements (noticed in infancy), IgA (and sometimes IgE) deficiency, and profound sinopulmonary infection, from a defect in a cell-cycle-regulating kinase — the mechanistic link between the immune defect and the neurological findings remains unclear.

Nezelof syndrome — autosomal recessive cellular immunodeficiency from thymic hypoplasia, presenting with chronic diarrhoea, viral/fungal infection, and failure to thrive.

Disorders of Phagocytosis

Chronic granulomatous disease (CGD) — inherited defects in NADPH oxidase components block the oxidative burst that generates microbicidal free radicals, predisposing specifically to catalase-positive pyogens (staphylococci, Pseudomonas, coliforms) since catalase-negative organisms like streptococci/pneumococci are handled fine. Two genetic forms exist: X-linked (70%, membrane oxidase component defective) and autosomal recessive (cytoplasmic component defective). Excessive inflammatory reaction produces gingivitis, lymphadenopathy, and nonmalignant granulomas. The nitroblue tetrazolium (NBT) reduction test screens for NADPH oxidase deficiency.

Myeloperoxidase deficiency — a common genetic defect (quantity or function) causing immune deficiency and recurrent infection, especially with Candida albicans.

Chediak–Higashi syndrome — autosomal recessive; defective phagosome-lysosome fusion (mutation in LYST, which regulates lysosomal trafficking) impairs bacterial killing despite normal phagocytosis, producing recurrent severe pyogenic infection alongside albinism (melanocyte defect), neurological abnormalities, bleeding tendency (platelet defect), and aggressive non-malignant lymphoid organ infiltration. Phagocytes show giant granules that cannot kill engulfed bacteria.

Leukocyte adhesion deficiency (LAD) — rare autosomal recessive defect in the β2 integrin (CD18) or fucosyltransferase, impairing leukocyte (especially neutrophil) chemotaxis and predisposing to bacterial and fungal infection.

Lazy leukocyte syndrome — idiopathic neutrophil chemotaxis defect causing gingivitis, abscesses, pneumonia, and neutropenia.

Job’s syndrome (Hyper-IgE syndrome) — rare, from STAT3 or DOCK8 mutations impairing neutrophil chemotaxis, presenting with eczema, recurrent staphylococcal skin abscesses, recurrent lung infection (with pneumatocele formation), eosinophilia, and markedly elevated serum IgE.

Complement deficiencies are covered under the Complement System topic.

Secondary Immunodeficiencies

Also called acquired immunodeficiencies, these are more common overall than primary immunodeficiency and arise secondary to: malnutrition (inadequate immunoglobulin synthesis), ageing (immune senescence), infections that themselves deplete lymphocytes (most importantly HIV/AIDS), underlying bone marrow/blood malignancy (leukaemia, lymphoma, multiple myeloma), proteinuric renal disease (loses immunoglobulin in urine), sarcoidosis, immunosuppressive medication, and chemotherapy/radiotherapy.

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