Immunology
Immunology covers primary immunodeficiency diseases — inherited or acquired defects in the immune system's ability to defend against infection, regulate inflammation, or prevent autoimmunity.
- Ataxia-Telangiectasia (AT) — autosomal recessive ATM gene defect; cerebellar degeneration, conjunctival telangiectasias, combined immunodeficiency, extreme cancer susceptibility, radiation hypersensitivity
- Chronic Granulomatous Disease (CGD) — NADPH oxidase defect; phagocytes cannot kill catalase-positive bacteria and fungi; recurrent life-threatening infections, granuloma formation
- Common Variable Immunodeficiency (CVID) — most common symptomatic antibody deficiency in adults; B-cell maturation failure, low IgG/IgA/IgM, recurrent sinopulmonary infections, autoimmunity, lymphoma risk
- DiGeorge Syndrome (22q11.2 Deletion) — most common chromosomal microdeletion (1:4,000 births); thymic hypoplasia, T-cell lymphopenia, cardiac outflow defects, hypocalcemia, 30% lifetime schizophrenia risk
- Hereditary Angioedema (HAE) — C1-inhibitor deficiency; unpredictable episodes of subcutaneous and submucosal swelling; laryngeal edema is life-threatening
- Hyper-IgE Syndrome (HIES / Job's Syndrome) — STAT3 or DOCK8 mutations; markedly elevated IgE, cold staphylococcal abscesses, eczema, pneumatoceles, retained primary teeth, Th17 deficiency
- IgA Deficiency — most common primary immunodeficiency overall; selective absence of IgA; recurrent mucosal infections, allergies, autoimmunity, anaphylaxis risk with blood products
- Mast Cell Activation Syndrome (MCAS) — mast cells degranulate too easily across multiple triggers; multisystem flushing, urticaria, GI, cardiovascular, and neurological symptoms; POTS/EDS triad overlap; responds to antihistamines and mast cell stabilizers
- Severe Combined Immunodeficiency (SCID) — see also Severe-Combined-Immunodeficiency; profound T and B cell failure; presents in infancy; fatal without hematopoietic stem cell transplantation
- Severe-Combined Immunodeficiency (detailed) — genetic subtypes, newborn screening, bubble boy disease, ADA deficiency, gene therapy advances
- Wiskott-Aldrich Syndrome (WAS) — X-linked WASp protein defect; eczema, thrombocytopenia with small platelets, combined immunodeficiency, autoimmunity, lymphoma risk
- X-Linked Agammaglobulinemia (XLA) — BTK mutation; B cells virtually absent; profound antibody deficiency from infancy; encapsulated bacteria, enterovirus encephalitis, no germinal centers
About Primary Immunodeficiency Diseases
Primary immunodeficiency diseases (PIDs) are a group of more than 450 distinct genetic disorders in which one or more components of the immune system fail to function correctly. They differ fundamentally from secondary immunodeficiencies (caused by HIV, chemotherapy, or malnutrition) in that the defect is inherited — present from birth in the genome, even if symptoms do not appear until later in childhood or adulthood.
PIDs span a wide spectrum of severity, from selective IgA deficiency (affecting 1 in 500 people, often without symptoms) to severe combined immunodeficiency (SCID), which is incompatible with normal life without stem cell transplantation. What unites them is that the immune system's ability to do one or more of its core jobs — recognizing pathogens, killing bacteria and fungi, clearing viruses, regulating inflammation, or distinguishing self from non-self — is impaired.
The Five Arms of Immunity and Their Defects
Understanding which arm of immunity is affected tells you almost everything about which infections a patient will suffer:
- Antibody deficiency (B-cell disorders): Susceptibility to encapsulated bacteria — Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis — and to enteroviruses. Examples: CVID, XLA, IgA deficiency.
- T-cell deficiency: Susceptibility to viral infections, fungi, Mycobacteria, Pneumocystis jirovecii, and intracellular pathogens. SCID combines T-cell and B-cell failure.
- Phagocyte defects: Susceptibility to catalase-positive bacteria (Staphylococcus aureus, Burkholderia, Serratia) and fungi (Aspergillus). Example: Chronic Granulomatous Disease.
- Complement deficiency: Susceptibility to encapsulated bacteria (early complement) or Neisseria meningitis (terminal complement). Example: Hereditary Angioedema (C1-INH deficiency).
- Immune dysregulation: Paradoxically, both too little immunity (infection susceptibility) and too much (autoimmunity, lymphoproliferation). Examples: AT, HIES, WAS.
The Diagnostic Delay Problem
The average time from first symptoms to confirmed PID diagnosis is 10–15 years for many conditions. This delay causes preventable organ damage — bronchiectasis, neurological deterioration, liver disease — that could be minimized with early diagnosis and treatment. The Jeffrey Modell Foundation's "10 Warning Signs of Primary Immunodeficiency" has been widely distributed to raise awareness among both patients and primary care physicians.
Treatment Principles
Treatment depends on the specific defect. Antibody deficiencies are treated with immunoglobulin replacement therapy (IVIG or SCIG), which provides passive protection against the infections the patient cannot prevent. SCID and some cases of Wiskott-Aldrich Syndrome are treated with hematopoietic stem cell transplantation (HSCT), which can be curative. DOCK8-deficient AR-HIES responds particularly well to HSCT. Newer treatments include gene therapy (approved for ADA-SCID) and targeted small-molecule therapies for specific genetic defects.