Hypersensitivity and Transplant Immunology

Hypersensitivity Reactions: Types I, II, III and IV

Overview and Classification

Hypersensitivity reactions are pathologic immune responses against otherwise harmless antigens, self-antigens, or persistent foreign antigens. They are classically divided into four Gell and Coombs types based on the dominant immune effector mechanism. Types I, II, and III are antibody-mediated; type IV is T-cell-mediated. Timing is high-yield: type I is immediate, type II and III usually occur over hours to days, and type IV is delayed, typically 48–72 hours after antigen exposure.

Type	Main mediator	Typical timing	Classic examples
I	IgE, mast cells, basophils, eosinophils	Minutes; late phase 4–24 hours	Anaphylaxis, allergic rhinitis, asthma, urticaria
II	IgG or IgM against cell-surface or matrix antigens	Hours to days	Autoimmune hemolytic anemia, Goodpasture syndrome, Graves disease
III	Immune complexes with complement activation	Days; serum sickness 1–2 weeks	SLE, poststreptococcal glomerulonephritis, serum sickness, Arthus reaction
IV	T lymphocytes: Th1, Th17, CD8+ cytotoxic T cells	48–72 hours	Contact dermatitis, tuberculin skin test, type 1 diabetes mellitus

Type I Hypersensitivity: Immediate, IgE-Mediated

Type I hypersensitivity begins with sensitization. An allergen is taken up by antigen-presenting cells and presented to naive CD4+ T cells, which differentiate into Th2 cells under the influence of IL-4. Th2 cells secrete IL-4 and IL-13, promoting class switching in B cells to IgE, and IL-5, promoting eosinophil activation. IgE binds the high-affinity Fc epsilon RI receptor on mast cells and basophils. On re-exposure, allergen cross-links bound IgE, triggering degranulation.

The immediate phase occurs within minutes and is mediated by preformed granule contents: histamine causes vasodilation, increased vascular permeability, bronchoconstriction, and pruritus; tryptase is a marker of mast-cell activation and may rise within 1–2 hours of anaphylaxis. Newly synthesized mediators include leukotrienes C4, D4, and E4, which cause prolonged bronchoconstriction, and prostaglandin D2, which causes bronchospasm and vasodilation. The late phase, occurring 4–24 hours later, is driven by eosinophils, Th2 cells, and cytokines, producing sustained edema and tissue injury.

Clinical examples include atopic dermatitis, allergic rhinitis, allergic asthma, food allergy, urticaria, and anaphylaxis. In anaphylaxis, guideline-based first-line pharmacology is intramuscular epinephrine into the anterolateral thigh: adults typically receive 0.3–0.5 mg of 1 mg/mL solution, repeated every 5–15 minutes as needed; pediatric dosing is 0.01 mg/kg up to 0.3 mg. Epinephrine activates alpha-1 receptors to reverse vasodilation and edema, beta-1 receptors to support cardiac output, and beta-2 receptors to bronchodilate and reduce mediator release.

Type II Hypersensitivity: Antibody-Mediated Cellular or Receptor Injury

Type II hypersensitivity is mediated by IgG or IgM directed against fixed antigens on cell surfaces or extracellular matrix. There are three major mechanisms. First, antibodies can opsonize cells, promoting phagocytosis via Fc receptors and C3b; examples include autoimmune hemolytic anemia, immune thrombocytopenia, and hemolytic disease of the newborn due to maternal anti-Rh IgG crossing the placenta. Second, antibodies can activate complement, producing C3a and C5a anaphylatoxins, neutrophil recruitment, and membrane attack complex-mediated injury; examples include transfusion reactions and Goodpasture syndrome, in which antibodies target the alpha-3 chain of type IV collagen in glomerular and alveolar basement membranes.

Third, antibodies can alter receptor function without necessarily destroying cells. In Graves disease, IgG stimulates the TSH receptor, causing hyperthyroidism. In myasthenia gravis, IgG blocks or promotes internalization of postsynaptic acetylcholine receptors, causing fatigable weakness. Direct antiglobulin testing, also called the direct Coombs test, detects IgG or C3 on patient erythrocytes and is high-yield for autoimmune hemolytic anemia and transfusion reactions.

Type III Hypersensitivity: Immune Complex Disease

Type III hypersensitivity results from circulating antigen-antibody complexes, usually containing IgG, depositing in tissues. Deposition is favored in high-pressure filtration sites such as glomeruli, synovia, skin vessels, and choroid plexus. Immune complexes activate complement, especially C3a and C5a, leading to mast-cell degranulation, neutrophil chemotaxis, and release of lysosomal enzymes and reactive oxygen species. Complement consumption may cause low C3 and C4, classically seen in active systemic lupus erythematosus.

Local type III disease is exemplified by the Arthus reaction, a localized immune-complex vasculitis that develops several hours after intradermal antigen exposure in a previously sensitized person. Systemic immune-complex disease includes serum sickness, typically 7–14 days after exposure to foreign proteins or certain drugs, with fever, urticaria, arthralgias, lymphadenopathy, and proteinuria. Poststreptococcal glomerulonephritis occurs after group A streptococcal infection and shows granular “lumpy-bumpy” immunofluorescence due to immune-complex deposition.

Type IV Hypersensitivity: Delayed, T-Cell-Mediated

Type IV hypersensitivity is antibody-independent and mediated by T cells. In the sensitization phase, antigen-presenting cells activate antigen-specific T lymphocytes. On re-exposure, memory T cells release cytokines and recruit inflammatory cells. Th1 cells secrete IFN-gamma, activating macrophages; Th17 cells secrete IL-17, recruiting neutrophils; CD8+ cytotoxic T cells directly kill target cells via perforin-granzyme pathways or Fas-Fas ligand interactions.

The prototype is the tuberculin skin test, read at 48–72 hours as induration, not erythema. Common positivity thresholds are 5 mm for high-risk immunosuppressed patients or recent contacts, 10 mm for moderate-risk groups such as recent immigrants or healthcare workers, and 15 mm for persons without risk factors. Contact dermatitis from poison ivy, nickel, or latex is another classic type IV reaction: small molecules act as haptens, bind skin proteins, and elicit T-cell responses. Granulomatous inflammation, as in tuberculosis or sarcoidosis, reflects persistent Th1-driven macrophage activation with epithelioid histiocytes and giant cells. Organ-specific autoimmune examples include type 1 diabetes mellitus, in which CD8+ T cells destroy pancreatic beta cells, and multiple sclerosis, involving T-cell-mediated CNS demyelination.

Transplant Immunology

Transplant immunology concerns immune recognition of genetically nonidentical tissue and the strategies used to prevent graft rejection. The central principle is that T cells are selected to recognize peptide presented by self major histocompatibility complex, but they can cross-react strongly with nonself human leukocyte antigen molecules, producing an unusually large alloreactive T-cell response: approximately 1%–10% of a recipient’s T cells may recognize donor alloantigen, far higher than the frequency for most microbial antigens.

Types of grafts and key histocompatibility concepts

Graft type	Definition	Immunologic consequence
Autograft	Tissue moved within the same individual, e.g., skin graft	No alloimmune rejection
Isograft	Between genetically identical individuals, e.g., monozygotic twins	Minimal rejection risk
Allograft	Between genetically different members of the same species	Typical clinical transplant; requires immunosuppression
Xenograft	Between different species	Very high innate and adaptive immune barriers

The most important alloantigens are HLA molecules, encoded on chromosome 6. Class I HLA-A, HLA-B, and HLA-C are expressed on nearly all nucleated cells and present endogenous peptides to CD8+ T cells. Class II HLA-DR, HLA-DQ, and HLA-DP are expressed on professional antigen-presenting cells and present exogenous peptides to CD4+ T cells. In solid organ transplantation, matching at HLA-A, HLA-B, and HLA-DR is especially emphasized; in hematopoietic stem cell transplantation, high-resolution matching commonly includes HLA-A, -B, -C, and -DRB1, often with additional DQ consideration.

Pretransplant immune risk assessment

Before transplantation, recipients are assessed for antibodies against donor antigens. ABO compatibility is critical because preformed anti-A or anti-B antibodies can immediately injure graft endothelium. Panel reactive antibody or calculated PRA estimates the percentage of potential donors to whom the recipient has anti-HLA antibodies; a cPRA of 80% means the recipient is predicted to be incompatible with about 80% of donors. Donor-specific antibodies are antibodies directed against that particular donor’s HLA. A positive crossmatch is a major contraindication to routine transplantation because it predicts antibody-mediated injury. Classic complement-dependent cytotoxicity crossmatch detects complement-fixing antibodies; flow cytometric crossmatch is more sensitive.

Allorecognition mechanisms

• Direct allorecognition: recipient T cells recognize intact donor HLA molecules on donor antigen-presenting cells. This is especially important in early acute rejection because donor dendritic cells migrate from the graft to lymph nodes and activate recipient T cells.
• Indirect allorecognition: recipient antigen-presenting cells process donor HLA proteins and present donor-derived peptides on recipient self HLA to recipient T cells. This contributes to chronic rejection and antibody formation.
• Costimulation: naive T-cell activation requires signal 1 through the T-cell receptor and signal 2, commonly CD28 binding B7. Blocking costimulation is a therapeutic concept; belatacept is a CTLA-4–Ig fusion protein that binds B7 and inhibits CD28 signaling.

Rejection patterns in solid organ transplantation

Type	Timing	Mechanism	Pathology and high-yield clues
Hyperacute rejection	Minutes to hours	Preformed IgG or IgM against ABO or donor HLA; complement activation	Endothelial injury, fibrinoid necrosis, neutrophils, thrombosis, graft cyanosis; prevented by ABO matching and negative crossmatch
Acute cellular rejection	Days to weeks, but can occur later with inadequate immunosuppression	Recipient T cells attack donor parenchyma and endothelium	Lymphocytic infiltrates; kidney: tubulitis and endarteritis; heart: interstitial lymphocytes with myocyte injury
Acute antibody-mediated rejection	Days to months	De novo or anamnestic donor-specific antibodies activate complement	Microvascular inflammation, capillaritis, thrombosis; C4d deposition suggests classical complement activation
Chronic rejection	Months to years	Repeated immune injury, indirect allorecognition, cytokine-driven smooth muscle proliferation and fibrosis	Progressive luminal narrowing, intimal fibrosis, interstitial fibrosis, graft dysfunction; often irreversible

Pathology grading systems are organ-specific. For kidney transplantation, the Banff classification scores lesions such as interstitial inflammation, tubulitis, glomerulitis, peritubular capillaritis, arteritis, chronic interstitial fibrosis, tubular atrophy, and C4d staining. Step 1 emphasis is not memorizing Banff scores, but recognizing that rejection is diagnosed by biopsy pattern plus serology, especially donor-specific antibodies.

Immunosuppressive pharmacology

Drug class	Examples and typical transplant dosing ranges	Mechanism	High-yield toxicities
Calcineurin inhibitors	Tacrolimus 0.05–0.1 mg/kg/day PO divided every 12 h; trough often 5–15 ng/mL. Cyclosporine 5–10 mg/kg/day; trough often 100–400 ng/mL	Inhibit calcineurin, preventing NFAT activation and IL-2 transcription	Nephrotoxicity, hypertension, neurotoxicity; tacrolimus causes diabetes, cyclosporine causes gingival hyperplasia and hirsutism
Antimetabolites	Mycophenolate mofetil 1 g PO twice daily; azathioprine 1–2 mg/kg/day	Mycophenolate inhibits inosine monophosphate dehydrogenase, blocking de novo guanine synthesis in lymphocytes; azathioprine inhibits purine synthesis	Myelosuppression, infections; mycophenolate is teratogenic and causes gastrointestinal toxicity
mTOR inhibitors	Sirolimus commonly 2–5 mg/day; trough often 5–15 ng/mL	Blocks IL-2 signal transduction by inhibiting mTOR, preventing T-cell proliferation	Hyperlipidemia, thrombocytopenia, impaired wound healing; relatively less nephrotoxic than calcineurin inhibitors
Corticosteroids	Prednisone maintenance often 5–10 mg/day; acute rejection pulses may use methylprednisolone 500–1000 mg IV daily for 3 days	Broad inhibition of NF-κB, cytokines, macrophages, and lymphocyte activation	Hyperglycemia, osteoporosis, infection, Cushingoid features
Biologic induction or rejection therapy	Basiliximab 20 mg IV on day 0 and day 4; antithymocyte globulin often 1.5 mg/kg/day IV for several doses	Basiliximab blocks CD25, the IL-2 receptor α-chain; antithymocyte globulin depletes T cells	Infusion reactions, leukopenia, opportunistic infections; cytokine release is important with T-cell–depleting agents

Current transplant practice generally uses combination therapy to block multiple steps: T-cell activation, cytokine production, and clonal expansion. Landmark evidence supporting calcineurin inhibition includes the introduction of cyclosporine in the 1980s, which markedly improved 1-year renal allograft survival; modern kidney graft 1-year survival commonly exceeds 90% in many registries. For Step 1, the essential concept is mechanistic: preventing rejection requires suppressing adaptive immunity while increasing susceptibility to opportunistic infection and malignancy, especially virus-driven cancers such as post-transplant lymphoproliferative disorder associated with Epstein-Barr virus.

Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is an immunologic complication in which immunocompetent donor T lymphocytes recognize recipient tissues as foreign and attack them. It is classically associated with allogeneic hematopoietic stem cell transplantation (HSCT), but can also occur after transfusion of nonirradiated cellular blood products in susceptible patients. Mechanistically, GVHD is a type IV hypersensitivity reaction: tissue injury is mediated predominantly by T cells and macrophage-activating cytokines rather than by antibody or immune complexes.

Core Pathogenesis

Three conditions are required for GVHD: the graft contains immunologically competent cells, the recipient expresses histocompatibility antigens absent from the donor, and the recipient is unable to eliminate the donor immune cells. Even when HLA matching is close, donor T cells can recognize minor histocompatibility antigens, which are polymorphic peptides presented on shared HLA molecules.

1. Conditioning phase: chemotherapy and/or radiation used before HSCT damages host tissues, especially gut mucosa, releasing danger signals and inflammatory cytokines such as TNF-α, IL-1, and IL-6. Bacterial products such as lipopolysaccharide can cross damaged mucosa and activate host antigen-presenting cells.
2. Donor T-cell activation: donor CD4⁺ and CD8⁺ T cells recognize recipient HLA or minor antigens on antigen-presenting cells. Costimulation and IL-2 drive clonal expansion.
3. Effector phase: cytotoxic T cells injure epithelium via perforin-granzyme and Fas-FasL pathways; Th1/Th17 cytokines recruit macrophages and neutrophils, amplifying tissue damage.

The same donor alloreactivity may also produce a beneficial graft-versus-leukemia effect, in which donor immune cells destroy residual malignant hematopoietic cells. Thus, excessive immunosuppression can reduce GVHD but may increase relapse risk.

Acute GVHD

Acute GVHD traditionally occurs within the first 100 days after transplant, although “late acute GVHD” can occur later, especially during tapering of immunosuppression. The classic target organs are skin, gastrointestinal tract, and liver.

Organ	Classic Findings	High-Yield Mechanism
Skin	Pruritic or painful maculopapular rash, often involving palms, soles, face, or trunk; severe cases resemble toxic epidermal necrolysis	Donor T-cell attack on basal keratinocytes
GI tract	Watery or bloody diarrhea, abdominal pain, ileus; severe disease may exceed 1500 mL/day stool output	Crypt epithelial apoptosis and mucosal barrier disruption
Liver	Cholestatic hepatitis with elevated bilirubin and alkaline phosphatase	Injury to small bile duct epithelium

Acute GVHD is staged by organ severity and combined into an overall grade. USMLE-relevant patterns are more important than memorizing every staging detail, but numerical thresholds are commonly tested.

Stage	Skin	Liver: Total Bilirubin	GI: Adult Diarrhea Volume
1	Rash <25% body surface area	2–3 mg/dL	500–999 mL/day
2	25–50% body surface area	3.1–6 mg/dL	1000–1500 mL/day
3	>50% body surface area	6.1–15 mg/dL	>1500 mL/day
4	Generalized erythroderma with bullae/desquamation	>15 mg/dL	Severe pain, ileus, or grossly bloody stool

Overall acute GVHD grades range from I to IV. Grade I is mild, usually skin-limited; grades III–IV indicate severe multiorgan disease and carry high nonrelapse mortality.

Chronic GVHD

Chronic GVHD usually develops after 100 days, but current NIH criteria emphasize clinical phenotype rather than timing alone. It resembles autoimmune and fibrosing disease. Findings include lichenoid or sclerodermatous skin changes, dry eyes and dry mouth resembling Sjögren syndrome, bronchiolitis obliterans, cholestatic liver disease, esophageal webs or strictures, fasciitis, and cytopenias.

NIH chronic GVHD scoring grades each involved organ from 0 to 3. Overall severity is mild if 1–2 organs have score 1, moderate if at least 1 organ has score 2 or three or more organs have score 1, and severe if any organ has score 3 or lung score is at least 2.

Risk Factors

• HLA mismatch, especially unrelated or haploidentical donors.
• Older recipient or donor age.
• Female donor to male recipient, partly due to donor immunity against Y-chromosome minor antigens.
• Peripheral blood stem cell grafts, which contain more T cells than bone marrow grafts.
• More intense conditioning, prior infections, and rapid tapering of immunosuppression.

Prevention and Treatment Pharmacology

GVHD prophylaxis targets donor T-cell activation. Common regimens include a calcineurin inhibitor plus an antiproliferative agent. Cyclosporine and tacrolimus inhibit calcineurin, preventing NFAT-mediated transcription of IL-2. Typical target troughs are approximately cyclosporine 150–400 ng/mL and tacrolimus 5–15 ng/mL, with nephrotoxicity, hypertension, neurotoxicity, and hyperkalemia as key adverse effects. Methotrexate, a folate antagonist, is often given on post-transplant days +1, +3, +6, and +11 at regimens such as 15 mg/m² on day +1 and 10 mg/m² subsequently.

Post-transplant cyclophosphamide, commonly 50 mg/kg on days +3 and +4, selectively eliminates rapidly proliferating alloreactive T cells and has enabled haploidentical transplantation. First-line treatment of clinically significant acute GVHD is systemic glucocorticoids, typically methylprednisolone 1–2 mg/kg/day. Steroid-refractory acute GVHD may be treated with ruxolitinib, a JAK1/2 inhibitor; the REACH2 trial reported day-28 overall response of about 62% with ruxolitinib versus 39% with best available therapy.

Transfusion-Associated GVHD

Transfusion-associated GVHD occurs when viable donor lymphocytes in cellular blood products engraft and attack the recipient. It is rare but often fatal, with mortality commonly cited as >90%. Risk is highest in severe T-cell immunodeficiency, HSCT recipients, Hodgkin lymphoma, intrauterine transfusion, and transfusion from HLA-homozygous relatives. Prevention is by gamma irradiation of cellular blood products, typically at least 25 Gy to the center of the bag with a minimum dose of about 15 Gy to all components, which prevents lymphocyte proliferation while preserving red cell and platelet function.