Pathology: Immunopathology, amyloidosis, genetic and environmental disease

🩻 Immunopathology, amyloidosis, genetic and environmental disease. The immune system can fail (immunodeficiency), overreact (hypersensitivity), attack self (autoimmunity) or reject transplanted tissue. Misfolded proteins accumulate as amyloid. Environmental agents - smoking, alcohol, occupational dusts, radiation, temperature and nutrition - cause much of the UK's preventable disease. This chapter covers the pathology of these processes with the clinical examples that appear repeatedly in exams.
Your four questions: Which arm of immunity is involved (antibody, complement, T cell, phagocyte)? Which hypersensitivity type explains the lesion? Is a protein deposit present (Congo red), and which precursor protein? What environmental or occupational exposure might be responsible?

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Hypersensitivity Reactions

Type	Mechanism	Timing	Examples
I - Immediate (IgE)	Allergen cross-links IgE on mast cells → histamine, leukotrienes, prostaglandins	Minutes	Anaphylaxis, allergic rhinitis, asthma, urticaria, food and drug allergy, atopic eczema (partly)
II - Antibody-mediated (cytotoxic)	IgG/IgM against cell or matrix antigens → complement, phagocytosis, ADCC or receptor dysfunction	Hours–days	Autoimmune haemolytic anaemia, ITP, haemolytic disease of the newborn, transfusion reactions, Goodpasture's (anti-GBM), pemphigus, Graves' disease (stimulating TSH receptor antibodies), myasthenia gravis (blocking AChR antibodies), rheumatic fever, pernicious anaemia, hyperacute rejection
III - Immune complex	Antigen–antibody complexes deposit in vessels, glomeruli and joints → complement activation (low C3, C4) → neutrophils	Days–weeks	SLE, post-streptococcal glomerulonephritis, serum sickness (antivenom, monoclonal antibodies, some drugs), extrinsic allergic alveolitis (with type IV), polyarteritis nodosa (hepatitis B), cryoglobulinaemia (hepatitis C), reactive arthritis, Arthus reaction
IV - Delayed (T cell-mediated)	Sensitised T cells release cytokines and activate macrophages, or cytotoxic T cells kill targets	48–72 hours	Contact dermatitis (nickel, poison ivy), Mantoux/tuberculin test, TB granulomas, sarcoidosis, type 1 diabetes, multiple sclerosis, coeliac disease, Hashimoto's thyroiditis, acute and chronic transplant rejection, SJS/TEN, DRESS, GVHD

• Anaphylaxis - IM adrenaline 0.5 mg (500 micrograms, 1:1000) in adults, repeated after 5 minutes if needed; mast cell tryptase at about 1–2 hours and at 24 hours confirms mast cell degranulation; refer to allergy clinic; adrenaline auto-injectors (two) (Resuscitation Council UK 2021).

Autoimmunity and Autoantibodies

• Loss of self-tolerance - genetic susceptibility (HLA associations) plus environmental triggers (infection - molecular mimicry, drugs, smoking, UV light, hormones - female predominance).

HLA	Associated disease
HLA-B27	Ankylosing spondylitis, reactive arthritis, psoriatic and IBD-associated spondyloarthritis, anterior uveitis
HLA-DR3	Type 1 diabetes, SLE, Graves', coeliac, Addison's, myasthenia gravis
HLA-DR4	Rheumatoid arthritis, type 1 diabetes
HLA-DQ2 / DQ8	Coeliac disease (negative predictive value - absence nearly excludes it)
HLA-B51	Behçet's disease
HLA-DR2 (DR15)	Multiple sclerosis, narcolepsy, Goodpasture's
HLA-B*57:01 / B*58:01 / B*15:02	Abacavir / allopurinol / carbamazepine hypersensitivity
Autoantibody	Disease
ANA	SLE (sensitive, not specific), other connective tissue diseases, autoimmune hepatitis
Anti-dsDNA, anti-Smith	SLE (specific; dsDNA tracks activity and nephritis)
Anti-histone	Drug-induced lupus (hydralazine, procainamide, isoniazid, minocycline, anti-TNF)
Anti-Ro (SSA), anti-La (SSB)	Sjögren's; SLE; congenital heart block and neonatal lupus
Anti-centromere	Limited cutaneous systemic sclerosis (CREST)
Anti-Scl-70 (topoisomerase), anti-RNA polymerase III	Diffuse systemic sclerosis (lung fibrosis; renal crisis)
Anti-Jo-1	Antisynthetase syndrome (myositis, ILD, mechanic's hands)
Anti-CCP, rheumatoid factor	Rheumatoid arthritis (anti-CCP more specific and predicts erosions)
c-ANCA (PR3)	Granulomatosis with polyangiitis
p-ANCA (MPO)	Microscopic polyangiitis, EGPA; also UC and PSC
Anti-GBM	Goodpasture's disease
Anti-mitochondrial (M2)	Primary biliary cholangitis
Anti-smooth muscle, anti-LKM1	Autoimmune hepatitis types 1 and 2
Anti-tTG IgA, anti-endomysial	Coeliac disease (check total IgA)
Anti-TPO	Hashimoto's thyroiditis
TSH receptor antibody (TRAb)	Graves' disease
Anti-GAD, anti-IA2, anti-ZnT8	Type 1 diabetes, LADA
Anti-AChR, anti-MuSK	Myasthenia gravis
Anti-intrinsic factor, anti-parietal cell	Pernicious anaemia
Anti-phospholipase A2 receptor (PLA2R)	Primary membranous nephropathy
Anti-aquaporin-4, anti-MOG	Neuromyelitis optica, MOG antibody disease

Immunodeficiency

• Suspect immunodeficiency with infections that are Severe, Persistent, Unusual or Recurrent (SPUR), or failure to thrive in children.

Defect	Examples	Typical infections
Antibody (B cell)	X-linked agammaglobulinaemia (BTK - boys after 6 months when maternal IgG wanes), common variable immunodeficiency (adults; autoimmunity, granulomas, lymphoma), selective IgA deficiency (commonest - often asymptomatic; anaphylaxis to blood products; false-negative coeliac IgA serology)	Encapsulated bacteria - sinopulmonary infections, bronchiectasis; enteroviruses; Giardia
T cell / combined	SCID (TREC newborn screening under evaluation in England since 2021), DiGeorge (22q11.2 deletion) - thymic aplasia, hypocalcaemia, conotruncal heart defects, cleft palate; Wiskott–Aldrich (eczema, thrombocytopenia with small platelets, infections); ataxia telangiectasia; HIV	Viruses (CMV, VZV), fungi (Candida, PCP), intracellular bacteria (mycobacteria); live vaccines dangerous; GVHD from non-irradiated blood
Phagocyte	Chronic granulomatous disease (NADPH oxidase), leucocyte adhesion deficiency, neutropenia (chemotherapy - commonest)	Staphylococci, Gram-negatives, Aspergillus; abscesses
Complement	C1 esterase inhibitor deficiency (hereditary angioedema - no urticaria, low C4), early components C1–C4 (SLE-like disease), C5–C9 (recurrent Neisseria infection); eculizumab (C5 inhibitor) - meningococcal vaccination required	Encapsulated bacteria; Neisseria
Splenic	Asplenia/hyposplenism (splenectomy, sickle cell disease, coeliac disease) - Howell–Jolly bodies	Overwhelming post-splenectomy infection (pneumococcus, Hib, meningococcus) - vaccines, lifelong or at least 2-year prophylactic penicillin/amoxicillin, emergency antibiotics, alert card

• Secondary (acquired) immunodeficiency is far commoner: drugs (steroids, chemotherapy, biologics, transplant immunosuppression), malignancy (CLL, myeloma, lymphoma - hypogammaglobulinaemia), HIV, malnutrition, diabetes, CKD, liver failure, protein loss (nephrotic syndrome), extremes of age.
• Initial tests: FBC and film, immunoglobulins (IgG, IgA, IgM), vaccine-specific antibody responses (tetanus, Hib, pneumococcus), lymphocyte subsets, complement (C3, C4, CH50), HIV test, neutrophil oxidative burst test.

Transplant Rejection and GVHD

Type	Timing	Mechanism	Features
Hyperacute	Minutes–hours	Preformed antibodies (ABO, HLA) - type II	Graft thrombosis; prevented by crossmatching
Acute cellular	Days–months (mostly first 6 months)	T cells (type IV)	Fever, graft dysfunction; responds to increased immunosuppression (steroid pulses)
Acute antibody-mediated	Weeks–months	Donor-specific antibodies; C4d deposition	Plasma exchange, IVIG
Chronic	Months–years	Mixed immune and non-immune - vascular intimal fibrosis	Kidney - interstitial fibrosis and tubular atrophy; heart - cardiac allograft vasculopathy (silent ischaemia - denervated heart); lung - bronchiolitis obliterans; irreversible

• Graft-versus-host disease - donor T cells attack the recipient (allogeneic stem cell transplant; non-irradiated blood in immunocompromised patients): skin (rash on palms, soles and ears), liver (cholestasis) and gut (diarrhoea); chronic GVHD resembles scleroderma and Sjögren's. Irradiated blood products prevent transfusion-associated GVHD.
• Immunosuppressant toxicities: calcineurin inhibitors (ciclosporin, tacrolimus - nephrotoxicity, hypertension, tremor, hyperkalaemia, hypomagnesaemia, diabetes (tacrolimus), gum hypertrophy and hirsutism (ciclosporin), many CYP3A4 interactions); mycophenolate (GI upset, marrow suppression, teratogenic); azathioprine (TPMT); sirolimus (poor wound healing, pneumonitis); steroids. Long-term risks - infection (CMV, BK virus, PCP), skin cancer (sun protection and annual skin checks), PTLD (EBV), cardiovascular disease.

Amyloidosis

• Amyloid - extracellular deposition of misfolded proteins in a β-pleated sheet fibrillar conformation; stains with Congo red showing apple-green birefringence under polarised light; resistant to degradation; disrupts organ function.

Type	Precursor protein	Associations	Organs
AL (primary)	Immunoglobulin light chains (λ more than κ)	Plasma cell dyscrasia - myeloma, MGUS, Waldenström's	Kidney (nephrotic syndrome), heart (restrictive cardiomyopathy - low-voltage ECG with thick walls), nerves (neuropathy, carpal tunnel, autonomic), macroglossia, periorbital purpura, hepatomegaly, GI
AA (secondary)	Serum amyloid A (acute phase protein)	Chronic inflammation - rheumatoid arthritis, IBD, bronchiectasis, chronic infection (TB, osteomyelitis, people who inject drugs), familial Mediterranean fever	Kidney (proteinuria, CKD), liver, spleen
ATTR (transthyretin)	Wild-type (age-related - older men) or hereditary variant TTR (e.g. V122I in people of West African ancestry; V30M)	Ageing; hereditary	Heart (HFpEF in older men, carpal tunnel years before, spinal stenosis, biceps tendon rupture), neuropathy (hereditary); tafamidis, acoramidis; patisiran/vutrisiran (silencers)
Aβ2-microglobulin	β2-microglobulin	Long-term haemodialysis	Carpal tunnel, joints, bone cysts
Aβ (amyloid-β)	Amyloid precursor protein	Alzheimer's disease, cerebral amyloid angiopathy (lobar haemorrhage in older people); trisomy 21	Brain
Islet amyloid (amylin)	IAPP	Type 2 diabetes	Pancreatic islets
Calcitonin-derived	Calcitonin	Medullary thyroid carcinoma	Tumour stroma

• Diagnosis: tissue biopsy (abdominal fat pad aspirate, rectal, or affected organ) with Congo red and typing (mass spectrometry or immunohistochemistry); serum free light chains and immunofixation (AL); technetium-labelled bone scintigraphy (DPD/PYP) for cardiac ATTR without biopsy (if no monoclonal protein); cardiac MRI; SAP scintigraphy; refer to the National Amyloidosis Centre (Royal Free, London).
• Treatment - treat the underlying cause: chemotherapy (daratumumab-based) ± stem cell transplant (AL), suppress inflammation (AA - anti-TNF, IL-1 or IL-6 blockade, colchicine in FMF), TTR stabilisers or silencers (ATTR), anti-amyloid antibodies in early Alzheimer's (lecanemab, donanemab - MHRA licensed 2024 but not recommended by NICE for NHS use).

Smoking and Alcohol

• Smoking - the leading preventable cause of death and illness in the UK: cancers (lung, head and neck, bladder, oesophagus, pancreas, kidney, cervix, stomach, AML), atherosclerosis (CHD, stroke, PAD, AAA, erectile dysfunction), COPD, Crohn's disease, peptic ulcer, osteoporosis, cataracts, macular degeneration, impaired wound healing, infertility; in pregnancy - low birth weight, preterm birth, stillbirth, placental abruption, sudden infant death; passive smoking - childhood asthma, otitis media, SIDS. Protective associations - ulcerative colitis, pre-eclampsia, Parkinson's disease (not a reason to smoke).
• Alcohol - UK low-risk guidance: no more than 14 units a week, spread over 3 or more days. Pathology:
  • Liver - steatosis (reversible) → alcoholic hepatitis (Mallory–Denk bodies, neutrophils) → cirrhosis (micronodular) → HCC.
  • GI - oesophagitis, Mallory–Weiss tears, varices, gastritis, acute and chronic pancreatitis, cancers (oral, pharyngeal, laryngeal, oesophageal, colorectal, liver, breast).
  • Nervous system - Wernicke–Korsakoff, cerebellar degeneration (anterior vermis - truncal ataxia), peripheral neuropathy, central pontine myelinolysis (rapid sodium correction), Marchiafava–Bignami, alcohol withdrawal seizures and delirium tremens, dementia.
  • Heart - dilated cardiomyopathy, AF ("holiday heart"), hypertension.
  • Others - macrocytosis, thrombocytopenia, myopathy, osteoporosis, gout, hypoglycaemia, ketoacidosis, testicular atrophy and gynaecomastia, fetal alcohol spectrum disorder (smooth philtrum, thin upper lip, short palpebral fissures, growth restriction, learning disability - no safe level in pregnancy).

Occupational Lung and Environmental Disease

Exposure	Disease	Features
Coal dust	Coal workers' pneumoconiosis; progressive massive fibrosis; Caplan's syndrome (with RA)	Upper lobe nodules
Silica (quarrying, sandblasting, stonemasonry, engineered stone worktops)	Silicosis	Upper lobe fibrosis, eggshell calcification of hilar nodes; increased TB risk and lung cancer; outbreaks from engineered stone fabrication
Asbestos (shipbuilding, construction, plumbing, insulation - pre-2000 buildings)	Pleural plaques (benign, commonest), diffuse pleural thickening, asbestosis (lower lobe fibrosis), mesothelioma, lung cancer	Long latency; industrial injuries disablement benefit; mesothelioma is a coroner's case
Beryllium (aerospace, electronics)	Berylliosis	Sarcoid-like granulomas
Organic antigens	Hypersensitivity pneumonitis - farmer's lung (Saccharopolyspora/mouldy hay), bird fancier's lung, humidifier lung, hot tub lung	Upper/mid zone; precipitins; avoid exposure
Isocyanates (spray painting), flour (bakers), latex, colophony (soldering), laboratory animals	Occupational asthma - commonest occupational lung disease	Symptoms improve away from work (weekends, holidays); serial peak flow; RIDDOR reportable
Cotton dust	Byssinosis	Monday chest tightness

• Carbon monoxide poisoning - faulty boilers and heaters, fires: headache, nausea, confusion (often household clusters, pets affected, better away from home); pulse oximetry falsely normal - measure carboxyhaemoglobin on a co-oximetry blood gas; 100% oxygen; hyperbaric oxygen in selected severe cases.
• Lead (old paint, pica in children, plumbing, battery recycling, Ayurvedic remedies) - anaemia with basophilic stippling, abdominal colic, neuropathy (wrist drop), encephalopathy, gum lead line; chelation.
• Air pollution (PM2.5, NO₂) - asthma, COPD exacerbations, cardiovascular disease, lung cancer; first UK death certificate citing air pollution (2020, Ella Adoo-Kissi-Debrah).

Physical Injury - Heat, Cold, Radiation, Electricity

• Heat: heat exhaustion (dehydration, temperature <40°C, intact mental state) versus heat stroke (core temperature >40°C with CNS dysfunction - rhabdomyolysis, DIC, AKI, liver failure - rapid active cooling); burns (superficial, partial thickness - blisters, full thickness - painless, white or leathery; Lund and Browder chart; inhalation injury - CO and cyanide).
• Cold: hypothermia (core <35°C - J waves (Osborn waves) on ECG, bradycardia, arrhythmias; "not dead until warm and dead"), frostbite, trench (immersion) foot, chilblains (pernio).
• Ionising radiation: acute radiation syndrome (haematopoietic, GI, neurovascular - dose-dependent), local effects of radiotherapy - acute (mucositis, skin erythema, diarrhoea, cystitis) and late (fibrosis, endarteritis obliterans - poor healing, strictures, radiation pneumonitis and fibrosis, cardiac disease, hypothyroidism after neck radiotherapy, second cancers, cataracts, infertility). Most sensitive tissues - bone marrow, gut epithelium, gonads, lens, fetus.
• Electrical injury - entry and exit wounds may look minor while deep muscle damage is extensive (rhabdomyolysis, compartment syndrome); arrhythmias (VF with low-voltage AC, asystole with high voltage and lightning); ECG and CK.
• Drowning, decompression illness (divers - "the bends", recompression chamber), altitude illness (acute mountain sickness, HAPE, HACE - descend, oxygen, dexamethasone/nifedipine).

Nutritional Disease and Obesity

• Protein-energy malnutrition - marasmus (energy deficiency - wasting, no oedema) and kwashiorkor (protein deficiency - oedema, fatty liver, skin and hair changes, "flaky paint" dermatosis); in the UK, malnutrition affects older people, chronic disease, cancer, eating disorders, alcohol dependence, people experiencing homelessness - screen with MUST (Malnutrition Universal Screening Tool).
• Refeeding syndrome - reintroducing nutrition after starvation → insulin surge drives phosphate, potassium and magnesium into cells → hypophosphataemia (respiratory failure, cardiac failure, arrhythmias, rhabdomyolysis, seizures), fluid retention, thiamine deficiency. NICE CG32: identify high-risk patients (BMI <16, little intake for >10 days, weight loss >15% in 3–6 months, low baseline electrolytes), start at 5–10 kcal/kg/day, give thiamine and vitamin B before feeding, monitor and replace electrolytes.
• Obesity (BMI ≥30; lower thresholds of ≥27.5 for South Asian, Chinese, other Asian, Middle Eastern, Black African and African-Caribbean people) - type 2 diabetes, hypertension, dyslipidaemia, CHD, stroke, MASLD (NAFLD), obstructive sleep apnoea, osteoarthritis, GORD, gallstones, PCOS, infertility, depression, cancers (13 types), VTE, idiopathic intracranial hypertension. Central (visceral) adiposity is most harmful (waist-to-height ratio >0.5). Treatment - lifestyle, GLP-1 receptor agonists (semaglutide, tirzepatide - NICE TA875, TA1026), bariatric surgery.
• Vitamin and trace element deficiencies - see the Biochemistry chapter.

At a Glance

Concept	Remember
Type I	IgE, mast cells - anaphylaxis
Type II	Antibody to cell/matrix - Graves', MG, Goodpasture's, AIHA
Type III	Immune complexes, low complement - SLE, PSGN, serum sickness
Type IV	T cells, 48–72 h - contact dermatitis, Mantoux, T1DM
C5–C9 deficiency or eculizumab	Neisseria infections
Asplenia	Encapsulated organisms - vaccines and antibiotics
Congo red + apple-green birefringence	Amyloid
AL	Light chains - heart, kidney, macroglossia
AA	Chronic inflammation - kidney
Wild-type ATTR	Older men, HFpEF, carpal tunnel
Silicosis	Eggshell calcification, TB risk
Asbestos	Plaques, asbestosis, mesothelioma
Refeeding	Hypophosphataemia - thiamine first, start slow

Spot the Diagnosis

• Haemoptysis and AKI in a young man; linear IgG along the glomerular basement membrane. → Goodpasture's (anti-GBM) disease - type II.
• Fever, rash, arthralgia and proteinuria 10 days after antivenom. → Serum sickness - type III.
• A man with rheumatoid arthritis for 25 years develops nephrotic syndrome. → AA amyloidosis.
• An 80-year-old man with HFpEF, bilateral carpal tunnel and low-voltage ECG with thick ventricular walls. → Wild-type ATTR cardiac amyloidosis - bone scintigraphy.
• A family with headaches that improve when they leave home; the dog is lethargic. → Carbon monoxide poisoning.
• A boy aged 8 months with recurrent pneumonias and very low immunoglobulins of all classes; no tonsils. → X-linked agammaglobulinaemia.

Exam-style Scenarios

• Scenario. A 23-year-old has had two episodes of meningococcal meningitis. What should be investigated?
  Answer: Complement deficiency - measure CH50 (classical pathway) and AP50 (alternative pathway), then individual components (terminal complement C5–C9, properdin). Also consider asplenia and antibody deficiency. Vaccinate (MenACWY, MenB) and consider prophylactic antibiotics.
• Scenario. A 70-year-old with heart failure, nephrotic syndrome, macroglossia and periorbital bruising. What tests will confirm the diagnosis?
  Answer: AL amyloidosis - serum free light chains, serum and urine immunofixation, bone marrow biopsy; tissue biopsy (fat pad or kidney) with Congo red and amyloid typing; cardiac staging (troponin, NT-proBNP, echo, cardiac MRI); refer to the National Amyloidosis Centre and haematology.
• Scenario. A severely malnourished patient with anorexia nervosa is admitted. Day 3 of feeding: breathless, weak, phosphate 0.3 mmol/L.
  Answer: Refeeding syndrome - IV phosphate replacement, check potassium and magnesium, reduce feeding rate temporarily, thiamine and vitamin B, cardiac monitoring, fluid balance; involve dietitians and follow MEED guidance (Medical Emergencies in Eating Disorders, RCPsych 2022).

Key Points

• Learn the four hypersensitivity types with two or three examples each.
• Match autoantibodies and HLA associations to diseases.
• Infection patterns point to the immune defect: antibody - encapsulated bacteria; T cell - viruses and fungi; phagocyte - staphylococci and Aspergillus; terminal complement - Neisseria.
• Amyloid: Congo red, apple-green birefringence; type it before treating.
• Occupational history matters - asbestos, silica, isocyanates, organic dusts.
• Refeeding syndrome: thiamine first, start slowly, monitor phosphate.

Guidelines and Further Reading

• Resuscitation Council UK: Emergency treatment of anaphylaxis (2021)
• British Society for Immunology / UK Primary Immunodeficiency Network: Recognising primary immunodeficiency
• National Amyloidosis Centre (Royal Free Hospital): diagnosis and management resources
• NICE CG32: Nutrition support for adults; RCPsych CR233: Medical emergencies in eating disorders (MEED)
• Health and Safety Executive: Occupational lung disease statistics and guidance
• UK Chief Medical Officers' low-risk drinking guidelines (2016)