Clinical Immunology, Hypersensitivity, Primary Immunodeficiencies & Transplant Rejection

MHC Class I (encoded by HLA-A, HLA-B, and HLA-C loci and stabilized by beta-2-microglobulin) is expressed on all nucleated cells and platelets (absent on mature red blood cells). Endogenous cytosolic proteins (viral proteins, tumor antigens) are ubiquitinated, degraded by the proteasome, pumped into the rough endoplasmic reticulum via the TAP transporter, loaded onto MHC Class I, and presented to CD8+ cytotoxic T lymphocytes (which kill target cells via perforin/granzyme B and FasL-Fas apoptosis). Viruses and tumors that downregulate MHC Class I to evade CD8+ T cells are eliminated by Natural Killer (NK) cells (CD16+ CD56+ large granular lymphocytes activated by IL-2, IL-12, and IFN-alpha/beta), which trigger cytotoxicity when inhibitory MHC Class I signals are missing or via Antibody-Dependent Cellular Cytotoxicity (ADCC) when CD16 binds the Fc region of IgG. MHC Class II (encoded by HLA-DP, HLA-DQ, and HLA-DR loci) is expressed on professional Antigen-Presenting Cells (APCs); exogenous antigens are endocytosed into acidified phagolysosomes, where cathepsins cleave the invariant chain down to CLIP, which HLA-DM replaces with the exogenous peptide for presentation to CD4+ helper T cells.

Naive CD4+ T cells polarize into four major lineages: (1) Th1 cells are induced by IL-12 and IFN-gamma via transcription factor T-bet, secreting IFN-gamma and IL-2 to activate macrophages and granuloma formation against intracellular pathogens (Mycobacterium tuberculosis, Listeria, Histoplasma); (2) Th2 cells are induced by IL-4 via transcription factor GATA-3, secreting IL-4 (drives B-cell class switching to IgE and IgG), IL-5 (activates eosinophils and drives IgA production), and IL-13 (airway mucus hypersecretion) against helminthic parasites and in atopic allergy; (3) Th17 cells are induced by TGF-beta + IL-6 (and IL-23) via transcription factor ROR-gamma-t, secreting IL-17 and IL-22 to recruit neutrophils to mucosal surfaces against extracellular bacteria and Candida; and (4) Regulatory T cells (Tregs; CD4+ CD25+ FOXP3+) are induced by TGF-beta + IL-2, secreting inhibitory cytokines IL-10 and TGF-beta to maintain peripheral self-tolerance (mutations in FOXP3 cause X-linked IPEX syndrome: Immune dysregulation, Polyendocrinopathy [neonatal Type 1 diabetes], Enteropathy, X-linked).

Early complement deficiencies (C1q, C2, C4) impair clearance of apoptotic debris and immune complexes, causing a >90% risk of Systemic Lupus Erythematosus (SLE)-like syndrome. Terminal complement deficiencies (C5–C9 MAC) cause recurrent disseminated Neisseria meningitidis and Neisseria gonorrhoeae bacteremia. Autosomal dominant deficiency of C1 esterase inhibitor causes Hereditary Angioedema, in which unregulated kallikrein cleaves high-molecular-weight kininogen into bradykinin, producing painless, non-pitting, non-pruritic mucosal and laryngeal edema without urticaria (screened via decreased serum C4 levels; ACE inhibitors are strictly contraindicated). Acquired somatic mutation of the PIGA gene in hematopoietic stem cells prevents synthesis of glycosylphosphatidylinositol (GPI) anchors for complement decay-accelerating factor (CD55) and MAC-inhibitory protein (CD59), causing Paroxysmal Nocturnal Hemoglobinuria (PNH)—characterized by intravascular complement-mediated hemolysis, pancytopenia, and hepatic/portal vein thrombosis (diagnosed via flow cytometry showing absent CD55/CD59 and treated with the C5-inhibitor monoclonal antibody eculizumab).

Type I (Immediate/IgE-mediated): Prior sensitization cross-links antigen-specific IgE bound to Fc-epsilon-RI receptors on mast cells and basophils; within minutes (early phase), preformed histamine and tryptase are released (causing vasodilation, bronchospasm, and urticaria), followed 6–24 hours later (late phase) by arachidonic acid synthesis of leukotrienes C4, D4, E4 and prostaglandins (e.g., anaphylaxis, allergic asthma, bee-sting reactions). Type II (Antibody-Mediated Cytotoxic/Functional): IgG or IgM binds directly to cell-surface or extracellular matrix antigens, causing (a) opsonization and complement/Fc-mediated destruction (autoimmune hemolytic anemia [positive Coombs test], immune thrombocytopenia, erythroblastosis fetalis, acute hemolytic transfusion reaction), (b) neutrophil-mediated inflammation (Goodpasture syndrome [linear anti-GBM IgG], rheumatic fever, bullous pemphigoid, pemphigus vulgaris), or (c) non-cytotoxic receptor dysfunction (Graves disease [TSH receptor-stimulating antibodies], Myasthenia Gravis [ACh receptor-blocking antibodies]). Type III (Immune Complex-Mediated): Soluble circulating antigen-IgG/IgM complexes deposit in vascular basement membranes and glomeruli, fixing complement (lowering serum C3/C4) and recruiting neutrophils via C5a to cause necrotizing vasculitis and fibrinoid necrosis (SLE, polyarteritis nodosa, post-streptococcal glomerulonephritis, serum sickness [fever, rash, arthralgias, proteinuria 5–10 days after systemic foreign protein/drug exposure], and the localized Arthus reaction [intradermal edema/necrosis 4–12 hours after booster vaccination in a patient with high pre-existing IgG titers]). Type IV (Delayed-Type Cell-Mediated): Sensitized CD4+ Th1 cells secrete IFN-gamma to activate macrophages (PPD tuberculin skin test induration at 48–72 hours, contact dermatitis to poison ivy/nickel, sarcoidosis granulomas) or CD8+ cytotoxic T cells directly lyse target cells (Type 1 diabetes mellitus beta-cell destruction, Stevens-Johnson syndrome/TEN, transplant cellular rejection, Hashimoto thyroiditis).

X-linked (Bruton) Agammaglobulinemia (XLA) is caused by a mutation in the BTK (Bruton tyrosine kinase) gene on the X chromosome, arresting bone marrow B-cell maturation at the pre-B-cell stage; boys present after 6 months of age with absent CD19+/CD20+ peripheral B cells, undetectable immunoglobulins of all classes, absent tonsils and palpable lymph nodes (lack of lymphoid germinal centers), and recurrent bacterial and enteroviral infections. Selective IgA Deficiency is the most common primary immunodeficiency overall; most patients are asymptomatic or experience recurrent sinopulmonary and Giardia lamblia infections, increased risk of celiac disease (requiring IgG-tTG testing because IgA-tTG is falsely negative), and life-threatening anaphylaxis upon transfusion of blood products containing trace donor IgA (requiring washed RBCs). Common Variable Immunodeficiency (CVID) presents in late adolescence or young adulthood (ages 20–35) with normal peripheral B-cell counts but defective plasma-cell differentiation and low IgG, IgA, and IgM, predisposing to bronchiectasis, autoimmune cytopenias, and gastric adenocarcinoma/non-Hodgkin lymphoma. Hyper-IgM Syndrome is most commonly an X-linked defect in T-cell CD40 ligand (CD40L / CD154); without CD40L-CD40 interaction, B cells cannot undergo class-switch recombination or somatic hypermutation and macrophages cannot be activated, resulting in markedly elevated IgM, absent IgG/IgA/IgE, absent germinal centers, and severe opportunistic Pneumocystis jirovecii and Cryptosporidium (sclerosing cholangitis) infections.

Severe Combined Immunodeficiency (SCID) is a neonatal medical emergency caused most commonly by an X-linked IL-2 receptor gamma-chain (IL2RG) mutation or autosomal recessive adenosine deaminase (ADA) deficiency (or RAG1/RAG2 V(D)J recombination failure). Infants present in the first months of life with chronic thrush, intractable diarrhea, failure to thrive, absent thymic shadow on chest radiograph, absent T-cell receptor excision circles (TRECs) on newborn screening, and profound T-cell and B-cell dysfunction; treatment requires strict avoidance of live vaccines, CMV-negative irradiated blood, antimicrobial prophylaxis, and urgent hematopoietic stem cell transplantation. Wiskott-Aldrich Syndrome is an X-linked mutation in the WASp gene (preventing actin cytoskeleton reorganization in hematopoietic cells), presenting with the classic WATER triad: Wiskott-Aldrich, Thrombocytopenia with small platelets (microthrombocytopenia, distinguishing it from ITP which has large platelets), Eczema, and Recurrent pyogenic/opportunistic infections, with a signature serum immunoglobulin profile of low IgM and elevated IgE and IgA.

Chronic Granulomatous Disease (CGD) is an X-linked recessive (gp91phox; 70%) or autosomal recessive deficiency of NADPH oxidase, abolishing the phagocytic respiratory burst. Neutrophils can still kill catalase-negative bacteria (such as Streptococcus) because the bacteria generate their own metabolic H2O2, which host myeloperoxidase converts into bleach. However, catalase-positive organisms destroy their own H2O2, leaving CGD neutrophils completely devoid of reactive oxygen intermediates and resulting in recurrent deep abscesses, pneumonia, osteomyelitis, and noncaseating granulomas caused by the 5 classic catalase-positive pathogens: Staphylococcus aureus, Pseudomonas/Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus (plus Candida and Salmonella). Diagnosis is confirmed by an abnormal dihydrorhodamine (DHR) flow cytometry test (absent green fluorescence) and a negative (colorless) nitroblue tetrazolium (NBT) reduction test; management includes lifelong TMP-SMX and itraconazole prophylaxis plus subcutaneous interferon-gamma. By contrast, Myeloperoxidase (MPO) deficiency is usually clinically asymptomatic (or causes mild Candida susceptibility in diabetics) with a normal DHR/NBT respiratory burst because NADPH oxidase remains intact.

Leukocyte Adhesion Deficiency Type 1 (LAD-1) is an autosomal recessive defect in the CD18 subunit of beta-2 integrins (LFA-1 and Mac-1), preventing neutrophil tight adhesion and diapedesis; infants present with delayed umbilical cord separation (>30 days after birth), severe omphalitis, recurrent necrotic bacterial skin and mucosal infections with complete absence of pus at the infection site, and striking peripheral neutrophilia (because neutrophils remain trapped inside the bloodstream). Chediak-Higashi syndrome is an autosomal recessive mutation in the LYST (CHS1) microtubule-trafficking gene, preventing phagosome-lysosome fusion; patients present with PLAIN: Progressive neurodegeneration, Lymphohistiocytosis, Albinism (partial oculocutaneous albinism), Infections (recurrent pyogenic Staphylococcus and Streptococcus), and Neutropenia with pathognomonic giant azurophilic granules inside neutrophils and platelets (causing mild bleeding/bruising) on peripheral blood smear. Hyper-IgE (Job) syndrome is an autosomal dominant STAT3 mutation impairing Th17 differentiation and neutrophil chemotaxis, remembered by FATED: coarse Facies, Abscesses (non-inflamed “cold” staphylococcal skin abscesses), retained primary Teeth (two rows of teeth), Elevated IgE and eosinophilia, and Dermatologic eczema (plus recurrent bone fractures).

Hyperacute rejection occurs within minutes to hours after vascular anastomosis opens (often while the surgeon is still in the operating room) because preformed recipient anti-donor antibodies (from prior blood transfusions, multiparity, or previous transplants, or ABO incompatibility) bind donor vascular endothelium, activating complement (Type II hypersensitivity) and triggering widespread fibrinoid necrosis, capillary thrombosis, and immediate ischemic graft mottling/infarction; the graft must be removed immediately (nephrectomy), and prevention relies on pre-operative cross-matching. Acute rejection occurs within weeks to months after transplantation (or following immunosuppression nonadherence) via two mechanisms: Acute Cellular Rejection (Type IV hypersensitivity: CD8+ cytotoxic T cells and CD4+ T cells infiltrate the parenchyma, causing renal tubulitis and endotheliitis/intimal arteritis) and Acute Antibody-Mediated (Humoral) Rejection (de novo donor-specific antibodies cause peritubular capillaritis and linear C4d complement deposition); acute rejection is reversible with high-dose intravenous corticosteroids, antithymocyte globulin, or plasmapheresis/rituximab. Chronic rejection develops insidiously over months to years as a mixed cellular and humoral response that stimulates vascular smooth muscle proliferation, resulting in concentric obliterative intimal fibrosis (transplant vasculopathy), interstitial fibrosis, and tubular/parenchymal atrophy (manifesting as bronchiolitis obliterans in lung transplants, accelerated diffuse coronary atherosclerosis in heart transplants, and vanishing bile duct syndrome in liver transplants); it is irreversible and refractory to immunosuppressive escalation.

Graft-Versus-Host Disease (GVHD) occurs primarily after allogeneic hematopoietic stem cell transplantation (or transplantation of lymphocyte-rich solid organs such as the liver or small bowel, or transfusion of non-irradiated blood to an immunocompromised SCID/DiGeorge patient) when immunocompetent graft CD8+ and CD4+ T cells recognize the host MHC as foreign and mount a systemic Type IV cytotoxic attack against rapidly dividing host epithelia. Patients present with the classic triad of a maculopapular rash (involving the palms, soles, and ears, progressing to desquamation), cholestatic jaundice/hepatomegaly (bile duct necrosis), and secretory/bloody diarrhea (intestinal crypt cell apoptosis). Maintenance transplant immunosuppression combines a calcineurin inhibitor (tacrolimus or cyclosporine, which inhibit IL-2 transcription; both cause nephrotoxicity, hypertension, and neurotoxicity), an antimetabolite (mycophenolate mofetil, which reversibly inhibits IMP dehydrogenase in purine synthesis), and corticosteroids, with mTOR inhibitors (sirolimus/everolimus) or costimulation blockers (belatacept, binding B7) used as calcineurin-sparing alternatives.

Live-attenuated vaccines (MMR, Varicella, Intranasal Influenza, Rotavirus, Yellow Fever, Oral Sabin Polio, BCG, Smallpox) replicate mildly in the host to elicit both potent CD8+ cellular and IgA/IgG humoral immunity without requiring boosters; however, they can revert to virulence and are strictly contraindicated in pregnancy and severe T-cell/combined immunodeficiencies (exception: MMR and Varicella are administered to HIV-positive patients if the CD4+ count is ≥200 cells/mm3). Inactivated/killed vaccines (Intramuscular Influenza, Salk Polio, Hepatitis A, Rabies), Subunit/Recombinant vaccines (Hepatitis B surface antigen, HPV L1 capsid, acellular Pertussis, Recombinant Zoster), and Toxoid vaccines (Tetanus and Diphtheria formaldehyded exotoxins) induce predominantly humoral IgG immunity, are completely safe in pregnancy and immunodeficiency, and require adjuvants (aluminum salts) and periodic booster doses. Polysaccharide vs. Conjugate vaccines: Pure capsular polysaccharide vaccines (PPSV23) activate B cells via T-cell-independent cross-linking, producing only short-lived IgM without memory or efficacy in children under 2 years old; covalently conjugating the polysaccharide capsule to an immunogenic carrier protein (such as diphtheria CRM197 toxoid in PCV13/15/20, Hib, and Meningococcal conjugate vaccines) recruits CD4+ helper T cells via MHC Class II, driving CD40-CD40L class switching to high-affinity IgG and robust immunologic memory in infants.

On board vignettes, specific autoantibodies clinch the diagnosis and predict organ-specific complications: in Systemic Lupus Erythematosus (SLE), anti-dsDNA correlates with disease activity and lupus nephritis, anti-Smith (anti-Sm, directed against snRNPs) is the most specific marker, and anti-histone antibodies are the hallmark of drug-induced lupus (hydralazine, procainamide, isoniazid, minocycline, anti-TNF agents). In Systemic Sclerosis (Scleroderma), anti-Scl-70 (anti-DNA topoisomerase I) identifies diffuse cutaneous disease with pulmonary fibrosis, whereas anti-centromere identifies limited cutaneous CREST syndrome with pulmonary arterial hypertension. In Sjogren syndrome, anti-Ro (SSA) and anti-La (SSB) carry a risk of congenital complete heart block in neonates of affected mothers.