Pathology chapters
Transplantation, immunodeficiency and autoimmunity
Why transplanted organs are rejected (hyperacute, acute and chronic rejection) and graft-versus-host disease, the main primary and secondary immunodeficiencies including HIV/AIDS, and how tolerance fails in autoimmune disease, with SLE and the key autoantibodies.
- Graft rejection is driven mainly by differences in HLA: hyperacute (minutes, preformed antibodies, for example ABO mismatch: thrombosis of graft vessels), acute (days to weeks, mainly T cells, the commonest, treatable with immunosuppression) and chronic (months to years, vascular intimal thickening and fibrosis). Graft-versus-host disease occurs when donor T cells (bone marrow transplant) attack the recipient's skin, liver and gut.
- Primary immunodeficiencies: Bruton agammaglobulinaemia (B cells, X-linked: bacterial infections after 6 months), DiGeorge (thymus, T cells, hypocalcaemia, heart defects; 22q11 deletion), SCID (both; ADA deficiency), selective IgA deficiency (the commonest, anaphylaxis with transfusions); HIV destroys CD4 T cells, AIDS when CD4 falls below 200/µL or an AIDS-defining illness appears.
- Autoimmunity is failure of self-tolerance (genes, especially HLA, plus triggers such as infection by molecular mimicry); SLE is the model systemic disease: ANA (sensitive), anti-dsDNA and anti-Smith (specific).
On this page
Transplantation
Types of graft
| Graft | Donor | Rejection |
|---|---|---|
| Autograft | Same person (skin graft) | None |
| Isograft (syngeneic) | Identical twin | None |
| Allograft | Another person of the same species | Yes, unless immunosuppressed |
| Xenograft | Another species (pig heart valve) | Yes |
Matching: ABO compatibility, HLA typing (HLA-A, B and DR matter most) and a cross-match (recipient serum tested against donor lymphocytes to find preformed antibodies). Corneal grafts rarely reject because the cornea lacks blood vessels (an immune-privileged site).
Types of rejection
| Type | Timing | Mechanism | Pathology |
|---|---|---|---|
| Hyperacute | Minutes to hours | Preformed antibodies (ABO, anti-HLA from earlier transfusions, pregnancies or grafts) bind graft endothelium → complement | Thrombosis of graft vessels, ischaemic necrosis; the graft turns cyanotic and mottled. Prevented by the cross-match; untreatable |
| Acute | Days to weeks (or months, especially if immunosuppression stops) | Cellular: CD8 and CD4 T cells; humoral: antibodies against graft vessels | Interstitial lymphocyte infiltrate, tubulitis (kidney), endotheliitis and vasculitis. The commonest type; reversible with more immunosuppression |
| Chronic | Months to years | T cells and antibodies; cytokines stimulate vessel wall cells | Intimal thickening of arteries (graft arteriosclerosis), interstitial fibrosis, atrophy; irreversible; the main cause of late graft loss |
Hyperacute = preformed antibodies, minutes. Acute = T cells, weeks. Chronic = vascular narrowing and fibrosis, years.
Immunosuppression: calcineurin inhibitors (ciclosporin, tacrolimus), mycophenolate, azathioprine, corticosteroids, anti-T-cell antibodies. Side effects: infections (CMV, fungi) and cancers (lymphoma linked to EBV, skin cancer).
Graft-versus-host disease (GVHD)
Donor T cells in the graft recognise the recipient as foreign. Seen mainly after bone marrow (haematopoietic stem cell) transplantation, and rarely after transfusion of unirradiated blood into an immunodeficient person.
- Acute GVHD: skin rash, liver damage (jaundice), gut damage (diarrhoea).
- Chronic GVHD: skin fibrosis resembling scleroderma, dry eyes and mouth, liver disease.
Prevented by irradiating blood products for at-risk patients and by T-cell depletion and immunosuppression.
Immunodeficiency
Clues to the type of defect
| Defect | Typical infections |
|---|---|
| B cells / antibodies | Recurrent pyogenic bacterial infections (pneumococcus, Haemophilus), sinus and chest infections; Giardia; enteroviruses |
| T cells | Viruses, fungi (Candida, Pneumocystis), intracellular bacteria (mycobacteria) |
| Phagocytes | Staphylococcus aureus, fungi (Aspergillus), poor pus |
| Complement (C5–C9) | Recurrent Neisseria |
Primary immunodeficiencies
| Disorder | Defect | Key features |
|---|---|---|
| X-linked agammaglobulinaemia (Bruton) | BTK gene; B cells fail to mature | Boys; recurrent bacterial infections starting after 6 months (when maternal IgG wanes); very low immunoglobulins, absent B cells; small tonsils and nodes |
| Selective IgA deficiency | IgA not made | The commonest primary immunodeficiency; often no symptoms; sinus, chest and gut infections; anaphylaxis with blood transfusion (anti-IgA antibodies); coeliac disease association |
| Common variable immunodeficiency | B cells fail to become plasma cells | Low immunoglobulins; presents in adolescence or adulthood; autoimmunity and lymphoma risk |
| DiGeorge syndrome | 22q11 deletion: failure of 3rd and 4th pharyngeal pouches | Absent thymus → T-cell deficiency; absent parathyroids → hypocalcaemia (tetany); heart defects (truncus arteriosus, tetralogy); facial anomalies |
| Severe combined immunodeficiency (SCID) | Both B and T cells | Severe infections from early infancy (candidiasis, Pneumocystis, persistent diarrhoea, failure to thrive). Commonest form is X-linked (common γ chain of IL-2 and other cytokine receptors); adenosine deaminase (ADA) deficiency is the commonest autosomal recessive form. Treated with bone marrow transplant; avoid live vaccines |
| Wiskott-Aldrich syndrome | X-linked (WAS protein) | Eczema, thrombocytopenia (small platelets), recurrent infections; low IgM |
| Ataxia-telangiectasia | ATM (DNA repair) | Ataxia, telangiectasia, IgA deficiency, lymphoma risk |
| Hyper-IgM syndrome | CD40 ligand | High IgM; low IgG, IgA, IgE; Pneumocystis |
| Chronic granulomatous disease, LAD, Chédiak-Higashi | Phagocyte defects | See acute inflammation |
Secondary (acquired) immunodeficiency
Much commoner than primary. Causes: malnutrition (the commonest worldwide), HIV, diabetes, cancer (leukaemia, lymphoma, myeloma), chemotherapy and steroids, splenectomy (encapsulated bacteria), old age, renal failure, burns.
HIV and AIDS
- HIV is a retrovirus that binds CD4 (with co-receptors CCR5 and CXCR4) on helper T cells, macrophages and dendritic cells.
- Transmission: sexual contact, blood (transfusions, reused needles and syringes), mother to child (pregnancy, delivery, breastfeeding).
- Course: acute retroviral syndrome (fever, rash, lymphadenopathy) → long clinically latent phase (virus keeps replicating in lymphoid tissue; CD4 falls slowly) → AIDS.
- AIDS is defined by a CD4 count below 200 cells/µL or an AIDS-defining illness.
- Opportunistic infections and tumours by CD4 level:
| CD4 (cells/µL) | Typical problems |
|---|---|
| Below 500 | Tuberculosis (any level), herpes zoster, oral candidiasis |
| Below 200 | Pneumocystis jirovecii pneumonia, Kaposi sarcoma (HHV-8), HIV encephalopathy |
| Below 100 | Toxoplasmosis of the brain, cryptococcal meningitis, oesophageal candidiasis |
| Below 50 | CMV retinitis, Mycobacterium avium complex, primary CNS lymphoma (EBV) |
- Diagnosis: combined antibody and p24 antigen tests (ELISA), confirmed by further tests; PCR for babies and viral load.
- Tuberculosis is the commonest serious opportunistic infection in HIV in countries like Pakistan.
Autoimmunity
Tolerance is the normal unresponsiveness to self antigens:
- Central tolerance: self-reactive T cells are deleted in the thymus and B cells in the bone marrow.
- Peripheral tolerance: anergy (no co-stimulation), regulatory T cells, deletion by apoptosis.
Autoimmune disease arises when tolerance fails, usually through:
- Genetic susceptibility: especially HLA genes (HLA-B27, DR3, DR4).
- Environmental triggers: infections (by molecular mimicry: streptococcal antigens resemble heart proteins in rheumatic fever), tissue injury exposing hidden antigens, drugs, UV light (SLE).
- Commoner in women.
Autoimmune diseases may be organ-specific (type 1 diabetes, Hashimoto thyroiditis, Graves, myasthenia gravis, pernicious anaemia) or systemic (SLE, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome).
Systemic lupus erythematosus (SLE)
A multisystem autoimmune disease, mainly in young women, caused by autoantibodies (especially against nuclear antigens) and immune complexes (type III hypersensitivity, with some type II).
- Skin: malar (butterfly) rash, photosensitivity, discoid rash, oral ulcers.
- Joints: non-erosive arthritis (the commonest feature).
- Kidney: lupus nephritis (immune complexes in glomeruli; "wire-loop" lesions); a major cause of death.
- Blood: haemolytic anaemia, leucopenia, thrombocytopenia.
- Serosa: pleuritis, pericarditis.
- Heart: Libman-Sacks (sterile) endocarditis.
- Nervous system: seizures, psychosis.
- Antiphospholipid antibodies: thrombosis, miscarriage.
Key autoantibodies
| Antibody | Disease |
|---|---|
| ANA | SLE (positive in nearly all: most sensitive, not specific) |
| Anti-dsDNA, anti-Smith | SLE (most specific); anti-dsDNA tracks kidney disease activity |
| Anti-histone | Drug-induced lupus (hydralazine, procainamide, isoniazid) |
| Anti-Ro (SS-A), anti-La (SS-B) | Sjögren syndrome; neonatal lupus (heart block) |
| Anti-centromere | Limited systemic sclerosis (CREST) |
| Anti-Scl-70 (topoisomerase I) | Diffuse systemic sclerosis |
| Rheumatoid factor, anti-CCP | Rheumatoid arthritis (anti-CCP more specific) |
| Anti-TPO (antimicrosomal), anti-thyroglobulin | Hashimoto thyroiditis |
| TSH receptor antibody | Graves disease |
| Anti-acetylcholine receptor | Myasthenia gravis |
| Anti-GBM | Goodpasture syndrome |
| c-ANCA (PR3) / p-ANCA (MPO) | Granulomatosis with polyangiitis / microscopic polyangiitis |
| Anti-tissue transglutaminase, anti-endomysial | Coeliac disease |
| Anti-mitochondrial | Primary biliary cholangitis |
Expect: graft types, hyperacute vs acute vs chronic rejection (timing, mechanism), GVHD organs, Bruton vs DiGeorge vs SCID vs IgA deficiency, infections that point to B-cell vs T-cell defects, HIV receptor and CD4 thresholds with opportunistic infections, central vs peripheral tolerance, molecular mimicry, SLE features, and autoantibody matches (ANA, anti-dsDNA, anti-Sm, anti-histone, anti-centromere, anti-CCP).
Quick revision
- Hyperacute: preformed antibodies, minutes. Acute: T cells, weeks. Chronic: intimal thickening, years.
- GVHD: donor T cells attack skin, liver, gut.
- Bruton: no B cells, boys, after 6 months. DiGeorge: no thymus, hypocalcaemia. SCID: both. IgA deficiency: commonest.
- HIV binds CD4 (+ CCR5); AIDS: CD4 < 200 or AIDS-defining illness.
- Autoimmunity: failure of tolerance; HLA genes plus triggers (molecular mimicry).
- SLE: ANA sensitive; anti-dsDNA and anti-Sm specific; anti-histone in drug-induced lupus.
Written by The House Job from standard pathology and immunology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).
FAQ
What causes hyperacute rejection?
Preformed antibodies in the recipient (for example against ABO or HLA antigens) that bind the graft's blood vessels within minutes, causing thrombosis.
What is graft-versus-host disease?
A condition, mainly after bone marrow transplantation, in which donor T cells attack the recipient's tissues, especially the skin, liver and gut.
What is the commonest primary immunodeficiency?
Selective IgA deficiency.
Which antibodies are most specific for SLE?
Anti-double-stranded DNA and anti-Smith antibodies.