Carcinogenesis & Immunopathology

Carcinogenesis

• Carcinogenesis is the process of initiation and promotion of cancer
• A carcinogen is any agent or substance that initiates cancer, e.g. chemicals, radiation, viruses
• The process involves changes in the genome of cells, including mutations, over-expression of genes, or loss of activity of gene products
• Mutations can be gross defects (e.g. translocations or breaks in chromosome arms) or single base-pair defects (e.g. point mutations, substitutions, deletions)

Four Classes of Normal Regulatory Genes

• Growth-promoting proto-oncogenes: normally code for proteins involved in the control of normal cell growth and differentiation
• Growth-inhibiting tumour suppressor genes: normally discourage cell growth or temporarily halt cell division to carry out DNA repair
• Genes that regulate apoptosis: normally allow programmed cell death to occur, preventing further cell growth
• Genes involved in DNA repair: normally allow repair of DNA following damage/mutations by stimuli
• Genetic alterations in these genes lead to abnormal uncontrolled proliferation of cells (i.e. tumour cells develop with growth and survival advantages over normal cells)

Aetiology of Cancer

• Tumours have a multifactorial aetiology in which carcinogens play only one part
• Body factors (intrinsic factors) and environmental factors (extrinsic factors) contribute to the causation of cancer
• Genetic makeup, racial background, climactic conditions, environmental agents, and diet may all contribute
• Explains why two people exposed to the same single carcinogen may not develop the same cancer

Intrinsic Factors

• Genetic factors: e.g. leukaemia, trisomy 21 in Down's syndrome, Philadelphia chromosome in chronic myeloid leukaemia, polyposis coli
• Racial and geographic factors: e.g. higher incidence of carcinoma of the breast in Australia compared to Japan
• Biological agents: viruses, e.g. hepatitis B virus → hepatocarcinoma, human herpes virus-8 → Kaposi's sarcoma, Epstein-Barr virus → Burkitt's lymphoma, human papilloma virus → cervical cancer

Immunopathology

• Disorders due to an abnormality in immune system function
• Subdivided into:
  • Immunodeficiencies (1° or 2°): inadequate immune response → increased susceptibility to infections and tumours
  • Hypersensitivities: excessive immune response → tissue damage
  • Autoimmune diseases: inappropriate immune response → tissue damage

Primary Immunodeficiency

• Present at birth due to genetic/congenital disorder
• Examples:
  • Agammaglobulinaemia (Bruton's disease): X-linked disorder, low/absent B-cells, normal T-cell function, severe bacterial infections
  • Congenital thymic aplasia (Di George syndrome): developmental disorder, absent thymus/functional tissue, often no parathyroids, absent T-cells, near normal B-cell function, severe viral, fungal, and protozoal infections
  • Combined immunodeficiency (Swiss-type syndrome): developmental disorder, absent lymphocyte stem cells in bone marrow, absent B-cells and T-cells, overwhelming recurrent infections of various types

Secondary Immunodeficiency

• Due to:
  • Ageing:  production of bone marrow stem cells
  • Infections: depress immunity non-specifically
  • Neoplasms: depress immunity
  • Immunosuppressive drugs: specifically lower immunity
  • Radiation: lymphocyte depletion due to radiation therapy, nuclear blasts
• Acquired Immune Deficiency Syndrome (AIDS): infection with the Human Immunodeficiency Virus (HIV), may be congenital or acquired, targets immune system and CNS, virus infects CD4+ cells

Hypersensitivities

• Type IV T cell mediated (delayed) hypersensitivity:
  • Tuberculin reaction (Mantoux test): +ve reaction > 72hrs
  • Contact dermatitis: due to nickel plated buckle, nickel plated stud, perfume, rubber soles
  • Mosquito bites, transplanted organ rejection
• Autoimmune diseases:
  • Organ-specific diseases: autoantibodies form against tissue (glandular tissues/epithelia/blood cells) → tissue damage, chronic inflammation
  • Systemic autoimmune diseases: multiple organs affected, e.g. systemic lupus erythematosus

Carcinogenesis

• Carcinogenesis is the process of initiation and promotion of cancer
• A carcinogen is any agent or substance that initiates cancer, e.g. chemicals, radiation, viruses
• The process involves changes in the genome of cells, including mutations, over-expression of genes, or loss of activity of gene products
• Mutations can be gross defects (e.g. translocations or breaks in chromosome arms) or a defect involving a single base-pair of DNA (e.g. point mutations; substitutions, deletions)

Biological Carcinogens

• Viruses are the only biological agents that can directly cause tumours
• Examples of virus-induced cancers:
  • Hepatitis B Virus → Hepatocarcinoma
  • Human Herpes Virus-8 → Kaposi's sarcoma
  • Epstein Barr Virus → Burkitt's lymphoma
  • Human Papilloma Virus → Cervical cancer

Immunopathology

• Disorders due to an abnormality in immune system function
• Subdivided into:
  • Immunodeficiencies (1° or 2°)
  • Hypersensitivities
  • Autoimmune diseases

Primary Immunodeficiencies

• Present at birth due to genetic/congenital disorder
• Examples:
  • Agammaglobulinaemia (Bruton's disease)
    • X-linked disorder
    • Low/absent B-cells (↓ antibody production)
    • Normal T-cell function
  • Congenital thymic aplasia (Di George syndrome)
    • Developmental disorder → absent thymus/functional tissue
    • Often no parathyroids → hypocalcaemia
    • Absent T-cells, no cellular immunity
    • Near normal B-cell function
  • Combined immunodeficiency (Swiss-type syndrome)
    • Developmental disorder
    • Absent lymphocyte stem cells in bone marrow
    • Absent B-cells & T-cells

Type I Immediate Hypersensitivity

• Allergen → IgE Antibody → Sensitized mast cell
• First exposure to allergen → no reaction
• 2nd & subsequent encounters with allergen → degranulation of mast cells → release of mediators of anaphylaxis (histamine, serotonin, etc.) → anaphylaxis (local or generalised effects)
• Examples:
  • Allergy to bee stings → blistering
  • Allergy to pollen → hay fever (allergic rhinitis)

Type II Antibody Mediated Hypersensitivity

• Due to IgG or IgM Abs causing direct cell damage & lysis
• Examples:
  • Erythroblastosis foetalis (haemolytic disease of the newborn)
  • Incompatible ABO blood transfusion reactions
  • Graves' disease
  • Myasthenia gravis

Type III Immune Complex Mediated Hypersensitivity

• Soluble antigen combines with specific Abs to form immune (Ag-Ab) complexes
• These circulate around body and localize in walls of vessels, leading to thrombosis, inflammation, tissue damage, necrosis
• Examples:
  • Serum sickness
  • Glomerulonephritis

Type IV T Cell Mediated (Delayed) Hypersensitivity

• No antibodies involved
• Sensitized T-cells, killer cells, activated macrophages and secretion of cytokines cause tissue damage
• Examples:
  • Contact dermatitis
  • Tuberculin reaction