Immunology Chapter: Tolerance and Hypersensitivity

Immunopathology

• Immunopathology is the study of the pathological effects of the immune system.
• It covers hypersensitivity reactions, autoimmune diseases, immunodeficiency syndromes, and amyloidosis.

Disorders of the Immune System

• Immunopathology disorders of the immune system are categorized into four broad headings: hypersensitivity reactions, autoimmune diseases, immunologic deficiency syndromes, and amyloidosis.
• Autoimmune disease involves immune reactions against self.
• Amyloidosis is a poorly understood disorder with an immunologic association.
• Immunologic deficiency syndromes result in an impaired immune system.

Hypersensitivity Reactions

• Normal immune reactions do not harm the host.
• Sometimes, immune reactions can be excessive, resulting in disease.
• People who mount normal immune responses are sensitized to that antigen.
• People who have excessive responses are hypersensitive.
• Environmental or self-antigens trigger hypersensitivity reactions ranging from trivial to fatal conditions.
• Imbalance between effector and control mechanisms contributes to hypersensitivity diseases.
• These diseases are often chronic, debilitating, and hard to treat.

Type I Hypersensitivity

• Also known as allergy.

• An allergen (antigen) binds to IgE antibodies on the surface of mast cells.

• Mast cells release mediators.

• Mediators result in vessel dilation, smooth muscle contraction, and persistent inflammation.

• The sequence of events follows an allergen's inhalation, ingestion, or injection.

• This is followed by TH2 cell stimulation, IL4 stimulation of B cells, resulting in IgE production and eosinophil recruitment.

• Allergen binding to mast cell IgE results in mast cell degranulation.

• Mediators (histamine, prostaglandin D2, leukotrienes, cytokines) cause immediate reactions (minutes after allergen re-exposure).

• Cytokines cause late reactions (2-24 hours after re-exposure characterized by inflammation and damage to the mucosal epithelium).

• Atopic allergies affect approximately 10% of the population.

• The symptoms of these local reactions depend on the route of allergen exposure: skin (itching, hives), gastrointestinal (diarrhea), and lungs (bronchoconstriction).

• Systemic reactions, such as anaphylaxis, may occur after exposure to allergens and exhibit severe symptoms like itching, hives, erythema, bronchoconstriction, and laryngeal obstruction, potentially leading to shock and death.

• A predisposition (atopy) to allergens is found to have higher IgE levels and elevated TH2 cells in individuals with allergies. Risk factors for susceptibility to allergies are linked to specific genes (5q31, close to HLA complex).

Type II Hypersensitivity

• Also known as antibody-mediated hypersensitivity.

• Antibodies bind to antigens on cell surfaces or extracellular matrices.

• This triggers phagocytosis, inflammation and cell dysfunction leading to tissue harm.

• Antibody-mediated cell damage can involve different mechanisms, depending on whether complement activation or cell-mediated cytotoxicity is involved.

• Example diseases include autoimmune hemolytic anemia, pemphigus vulgaris, Goodpasture syndrome, myasthenia gravis, and Graves disease.

Type III Hypersensitivity

• Also known as immune complex-mediated hypersensitivity.
• Antibodies bind to antigens forming complexes.
• The complexes circulate and deposit in vessels, activating inflammation.
• The end result is bad inflammation and necrotizing vasculitis.
• Systemic reactions (e.g., serum sickness) involve complexes forming in circulation and depositing in organs like kidneys, joints, and small vessels, causing inflammation and symptoms such as fever, joint pain, and proteinuria.
• Local reactions (e.g., Arthus reaction) involve complex formation at the site of antigen injection, leading to localized skin necrosis, edema, hemorrhage, and ulceration.
• Immune complexes can activate complement resulting in the attraction and activation of neutrophils, and monocytes that further damage the affected tissues.

Type IV Hypersensitivity

• Also known as T-cell-mediated hypersensitivity.
• Activated T cells release cytokines or directly kill cells.
• This process is normally used against intracellular pathogens (viruses, fungi, and parasites).
• However, it can lead to harmful responses in some cases, including inflammation, cell destruction, and granuloma formation.
• Delayed-type hypersensitivity (DTH), a type of cell-mediated immunity with a variable onset, is characterized by inflammation that occurs 24-72 hours after exposure to the antigen; macrophages play a key role in the T-cell-mediated immunity component.
• Direct cell cytotoxicity utilizes CD8+ T cells that may kill infected or abnormal cells and involves the detection of cell-surface antigens leading to the killing/destruction of these infected cells.
• A good example of DTH is the positive Mantoux test, where patients previously exposed to TB antigens injected into the skin exhibit reddening and induration.

Transplant Immunology

• Transplant rejection is a complex phenomenon involving both cell-mediated and antibody-mediated hypersensitivity reactions against histocompatibility molecules on the foreign graft.
• Transplantation can be autologous, syngeneic, or xenogeneic, depending on whether it involves the same individual, genetically identical individuals, or different species, respectively.
• MHC molecules in allografts (the transplanted organ) can be recognized directly by the host's T cells, or indirectly by host CD4+ T cells after the MHC molecules are processed and presented by the host's APCs.
• Classification of rejection can involve hyperacute rejection (occurring within minutes to hours post-transplantation in pre-sensitized individuals), acute rejection (occurring within days to weeks post-transplantation involving T-cell-mediated damage and antibody-mediated vascular damage), and chronic rejection (occurring months to years post-transplantation, mediated by T-cell reactions).
• Graft-versus-host disease (GVHD) occurs when immunologically competent T cells (or their precursors) from the donor's transplant attack the recipient's tissues, inducing a DTH or a cytototoxic effect, often appearing after bone marrow transplantation and some other solid organ transplants.

Autoimmune Diseases

• Autoimmune diseases involve the immune system attacking the body's own tissues or cells.

• Immunologic tolerance normally prevents the immune system from attacking self-antigens.

• The immune system's failure can result in autoimmune diseases.

• Genetic predisposition (HLA alleles and Fas genes) and environmental triggers (infection and tissue damage) are two primary causes of autoimmune disease breakdowns.

• These breakdowns can also result from defective tolerance or regulation, abnormal display of self-antigens and inflammation or an innate immune response.

• Examples of autoimmune disorders are systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren syndrome, and systemic sclerosis.

Immune Deficiencies

• Patients with immune deficiencies are more susceptible to infections and cancers.
• Several factors can lead to immune deficiencies: inherited/genetic disorders, acquired conditions (e.g., infections, immunosuppression), malnutrition, and damage or removal of organs.
• Types of infections vary dependent on the specific immune cell/molecular defect. Examples include bacterial infection (defect in Ig, C' or phagocytic cells), viral or fungal infections (in T-cell defects).
• Primary immune deficiencies are rare, genetic conditions that can affect any part of the immune system, leading to defects in lymphocyte maturation and function; this often results in infants with recurrent infections. Acquired or secondary deficiencies are more prevalent, induced by various factors, including defective lymphocyte maturation, defective immunoglobulin synthesis, depletion of lymphocytes by drugs or severe infections.

AIDS (Acquired Immunodeficiency Syndrome)

• AIDS is a retroviral disease caused by human immunodeficiency virus (HIV).

• HIV infection is characterized by depletion of CD4+ T cells and profound immunosuppression.

• This leads to opportunistic infections and secondary neoplasms.

• AIDS is a global health concern and it's estimated that there are approximately 1 million diagnosed cases in the USA.

• Epidemiology includes the recognition in 1981, the discovery of the virus 1984 and its role as a profound cause of disease worldwide mortality in Africa, and current cases worldwide.

• Transmission routes include sexual activity (most prevalent), parenteral transmission through infected blood and blood products (e.g., intravenous drug users, haemophiliacs), and vertical transmission from mother to child.

• Other methods like accidental exposure to infected needles or body fluids (with risk depending on variables such as volume, viral load, and exposed site) contribute to transmission.

• Etiology of AIDS involves a retrovirus from the lentivirus family with genetically related types (HIV-1 and HIV-II) and subgroups. The HIV-1 subgroups include M(major), O(outlier), and N(neither M nor O), with subtype B being the most common in Western Europe and the United States, while subtype E is more prevalent in Thailand.

• Pathogenesis includes virus infection of multiple tissues. Major targets include immune and nervous systems. CD4+ T-cell depletion results in functional impairments and increased vulnerability to opportunistic infections.

• Life cycle of HIV involves fusion of HIV membrane with cell membrane, internalization of viral RNA, reverse transcription to DNA, integration to host DNA, assembly of proteins, maturation, and budding and release of virions.

• Co-receptors such as CXCR4 and CCR5 play a significant role in HIV infection.

• Most HIV strains are transmitted by R5 strains.

• AIDS clinical features often range from mild acute illness to severe disease. Symptoms include fever, weight loss, chronic diarrhoea, generalized lymphadenopathy, opportunistic infections, neurologic disorders, and secondary neoplasms.

• Opportunistic infections are a significant cause of AIDS-related mortality, arising from reactivation of latent infections, oncogenic DNA viruses (e.g., Kaposi's sarcoma [KS] caused by Human Herpesvirus 8), and tumors.

• Infections include protozoal/helminthic infections (e.g. Cryptosporidiosis and Pneumocystosis), fungal infections (e.g., Candidiasis, Cryptococcosis), bacterial infections (e.g. Mycobacteriosis, Salmonella), viral infections (e.g. CMV, Herpes), and neoplasms.

• Diagnosis methods include antibody tests (ELISA and Western blot) and HIV RNA viral load.

• Treatment commonly involves antiretroviral therapy, including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors, among others.

Amyloidosis

• Amyloidosis is a disease associated with a number of inherited and inflammatory disorders.

• Characterized by extracellular deposits of fibrillar proteins, which leads to tissue damage and dysfunction.

• These fibrils result from the aggregation of misfolded proteins which are normally soluble.

• Approximately 20 to 23 different proteins can aggregate to form fibrils with an appearance designated as amyloid.

• The three most common fibril types are AL (derived from immunoglobulin light chains, often produced by monoclonal plasma cells), AA (a unique non-Ig protein derived from SAA or serum amyloid-associated protein synthesized in the liver), and Aβ (a core protein of cerebral plaques found in Alzheimer's patients, resulting from proteolysis of Amyloid Precursor Protein).

• Amyloid deposits can be found in various organs/systems, including the kidneys, spleen, liver, and heart, and usually manifest as an enlargement or decreased size, nonspecific symptoms (e.g., fatigue, fever) progressing to more specific symptoms relating to specific organ involvement.

• Prognosis depends on factors such as the type of amyloidosis and often correlated with median survival for two years in systemic cases.

Test your knowledge on central tolerance mechanisms in the immune system, including processes like anergy and apoptosis in lymphocytes. This quiz also covers hypersensitivity reactions, particularly the role of IgE and mast cells in Type I hypersensitivity. Prepare to delve into the intricacies of immune tolerance and the immune responses involved.