E. Path Week 5: Carcinogenesis-Immunopathology

Carcinogenesis

Tumor initiation and promotion occur via genetic alterations in four major gene classes: proto-oncogenes (promote normal cell growth), tumor suppressor genes (inhibit growth or allow DNA repair), apoptosis-regulating genes (control programmed cell death), and DNA repair genes (correct DNA damage).

Carcinogen

An agent capable of initiating cancer, including chemicals, radiation, and viruses.

Intrinsic carcinogenic factors

Genetic predisposition, hormonal influences, immune status, age, benign tumors.

Extrinsic carcinogenic factors

Chemicals, physical agents (e.g., radiation), biological agents (e.g., viruses).

Aflatoxins

A type of extrinsic carcinogen that can lead to hepatocellular carcinoma.

Human papillomavirus (HPV)

An extrinsic carcinogen that can lead to cervical carcinoma.

Asbestos

An extrinsic carcinogen that can lead to mesothelioma.

Primary immunodeficiency

Congenital disorders such as agammaglobulinemia (B-cell), thymic aplasia (T-cell), and combined immunodeficiencies (e.g., Swiss-type affecting both B and T cells).

Secondary immunodeficiency

Acquired causes include AIDS (T-cell), multiple myeloma (B-cell), immunosuppressive drugs and radiation (B & T cells), and neoplasms.

AIDS (Acquired Immunodeficiency Syndrome)

Caused by HIV, spread via blood, sexual contact, and body fluids. Targets CD4+ helper T cells and macrophages, reducing cell-mediated immunity.

AIDS-defining conditions

Opportunistic infections (e.g., oral thrush, Pneumocystis pneumonia), secondary neoplasms (e.g., Kaposi sarcoma, lymphoma), neurological disorders (e.g., AIDS dementia complex).

Type I hypersensitivity antibody

IgE.

Mechanism of Type I hypersensitivity

Initial allergen exposure produces IgE, which binds to mast cells. Upon re-exposure, allergen cross-links IgE, causing mast cell degranulation and release of histamine, leading to inflammation.

Examples of Type I hypersensitivity

Bronchial asthma (localized), anaphylactic shock (systemic).

Type II hypersensitivity antibodies

IgG and IgM.

Mechanism of Type II hypersensitivity

IgG or IgM binds to antigens on host cells, triggering complement activation or phagocytosis, leading to cell lysis or dysfunction.

Examples of Type II hypersensitivity

Incompatible blood transfusion, erythroblastosis fetalis (Rh incompatibility).

Prevention of erythroblastosis fetalis

Administer anti-Rh immunoglobulin to Rh-negative mothers near delivery to prevent maternal sensitization.

Receptor-mediated effects in Type II hypersensitivity

Graves' disease: Stimulation of TSH receptor; Myasthenia gravis: Inhibition of ACh receptor.

Type III hypersensitivity

Caused by immune complexes formed between soluble antigens and antibodies that deposit in tissues, triggering complement activation and inflammation.

Examples of Type III hypersensitivity

Post-streptococcal glomerulonephritis, serum sickness.

Clinical features of Type III hypersensitivity

Vasculitis, oedema, haematuria, albuminuria, glomerulonephritis.

Type IV hypersensitivity

Also called delayed-type or cell-mediated hypersensitivity. Involves sensitized T cells and macrophages.

Mechanism of Type IV hypersensitivity

Upon re-exposure, T cells release cytokines that recruit and activate immune cells, causing tissue damage. No antibodies involved.

Examples of Type IV hypersensitivity

Contact dermatitis, transplant rejection, mosquito bite reactions.

Autoimmune disorder

A condition in which the immune system attacks the body's own cells due to loss of self-tolerance.

Autoantigens

Self-components that provoke an autoimmune response.

Autoantibodies

Antibodies directed against self-antigens, causing tissue damage.

Triggers of autoimmune disorders

Can be genetic or environmental. Often unknown and may involve hypersensitivity reactions.

Organ-specific autoimmune disease

Target antigens confined to a single organ. Example: Hashimoto's thyroiditis.

Systemic autoimmune disease

Target antigens found in multiple organs. Example: Systemic lupus erythematosus (SLE).

Type II hypersensitivity

Hypersensitivity type with autoantibody-mediated receptor effects.

Mechanism in Graves' disease

Autoantibodies stimulate TSH receptors, increasing thyroid hormone production (Type II).

Mechanism in Myasthenia gravis

Autoantibodies block acetylcholine receptors at the neuromuscular junction, causing muscle weakness.

Chronic autoimmune atrophic gastritis

Autoantibodies against parietal cells and intrinsic factor lead to gastric atrophy and pernicious anemia.

Hashimoto's thyroiditis

Autoantibodies destroy thyroid tissue, replaced by lymphocytes, resulting in hypothyroidism.

Key features of systemic lupus erythematosus (SLE)

Anti-nuclear antibodies (ANA), malar rash, multisystem involvement (skin, kidneys, joints, CNS).

Organs commonly affected in SLE

Skin, joints, kidneys, brain, connective tissue.

Rheumatoid arthritis

Chronic autoimmune polyarthritis with joint damage, rheumatoid nodules, and T cell-mediated inflammation.

Rheumatic heart disease mechanism

Cross-reactive autoantibodies formed after group A streptococcal infection target heart tissues, forming Aschoff bodies and causing carditis.

Oedema

Extracellular fluid accumulation (interstitial).

Hydropic Change

Intracellular fluid accumulation.

Types of oedema

Localized and generalized.

Causes of localized oedema

Acute inflammation (e.g., burns), allergic reactions (e.g., bee stings).

Causes of generalized oedema

Right heart failure, renal disease (e.g., glomerulonephritis).

Ascites

Oedema fluid accumulation in the peritoneal cavity.

Reduced plasma osmotic pressure in oedema

Due to hypoproteinaemia.

Hormonal mechanism contributing to oedema

Activation of the renin-angiotensin-aldosterone system (RAAS), leading to sodium and water retention.

Oestrogen's role in oedema

Stimulates angiotensinogen secretion and promotes sodium retention.

Life-threatening oedema types

Pulmonary oedema and cerebral oedema.

Anasarca

Severe, generalized oedema affecting the entire body.

Hydrothorax

Fluid accumulation in the pleural cavity.

Hydropericardium

Fluid accumulation in the pericardial sac.

Lymphatic obstruction in parasitic infection

Caused by Wuchereria bancrofti, leading to elephantiasis.

Transudate

Non-inflammatory, low-protein oedematous fluid.

Oedema in kwashiorkor

Generalized oedema due to malnutrition and hypoalbuminaemia.