Disorders Associated with the Immune System: Hypersensitivity, Autoimmunity, Transplantation, Cancer, and Immunodeficiencies

Disorders Associated with the Immune System

Hypersensitivity

Hypersensitivity refers to an antigenic response that results in undesirable effects, occurring when an individual is sensitized by previous exposure to an antigen (allergen). There are four types of hypersensitivity reactions, each with distinct mechanisms and clinical manifestations.

• Type I (Anaphylactic) Reactions: - Occur within minutes after re-exposure to an antigen. - IgE antibodies bind to mast cells and basophils, leading to degranulation and release of mediators such as histamine, leukotrienes, and prostaglandins. - Systemic anaphylaxis can cause shock and death; treated with epinephrine. - Localized anaphylaxis affects specific regions (e.g., hay fever, asthma, food allergies). - Allergy skin tests and desensitization (producing IgG blocking antibodies) are used for diagnosis and prevention.

• Type II (Cytotoxic) Reactions: - Involve activation of complement by IgG or IgM antibodies bound to antigenic cells, causing cell lysis or damage. - ABO and Rh blood group systems are classic examples. - Hemolytic disease of the newborn (HDNB) occurs when an Rh-negative mother produces anti-Rh antibodies against an Rh-positive fetus. - Drug-induced cytotoxic reactions include immune thrombocytopenic purpura, agranulocytosis, and hemolytic anemia.

• Type III (Immune Complex) Reactions: - Antibodies react with soluble antigens, forming immune complexes that lodge in basement membranes and activate complement, causing inflammation. - Examples include Arthus reaction and serum sickness.

• Type IV (Delayed Cell-Mediated) Reactions: - Mediated by T cells; delayed hypersensitivity develops after a day or more. - Examples include tuberculosis skin test and allergic contact dermatitis (e.g., poison ivy, cosmetics, metals, latex).

The Hygiene Hypothesis

The hygiene hypothesis suggests that limiting exposure to pathogens may lower immune tolerance and the ability to cope with harmless antigens. Dysbiosis, or imbalance of microbiota, can lead to adverse effects such as inflammatory bowel diseases (IBDs) and allergies. Treatments include fecal transplants and whipworm therapy for Crohn's disease.

Autoimmune Diseases

Autoimmune diseases occur when the immune system responds to self-antigens, causing organ damage. Self-tolerance is normally maintained by clonal deletion of self-reactive T cells in the thymus. Loss of self-tolerance leads to autoimmunity, which can be cytotoxic, immune complex, or cell-mediated.

• Cytotoxic Autoimmune Reactions: - Multiple sclerosis: Autoantibodies, T cells, and macrophages attack myelin sheath of nerves.

• Immune Complex Autoimmune Reactions: - Systemic lupus erythematosus: Autoantibodies against DNA form immune complexes in kidneys. - Rheumatoid arthritis: Immune complexes deposit in joints, causing chronic inflammation.

• Cell-Mediated Autoimmune Reactions: - Type 1 diabetes: T cell destruction of insulin-secreting cells. - Psoriasis: T cells induce keratinocyte growth.

Reactions to Transplantation

Transplant rejection is mediated by T cells, macrophages, and complement-fixing antibodies. The HLA complex (human MHC) is crucial for tissue matching. Privileged sites (e.g., cornea) and privileged tissues (e.g., decellularized pig heart valves) do not provoke immune responses. Stem cells, both embryonic and adult, are used for tissue regeneration.

• Types of Grafts: - Autograft: One's own tissue - Isograft: Identical twin's tissue - Allograft: Tissue from another person - Xenotransplantation: Nonhuman tissue (e.g., "GalSafe" pigs)

• Immunosuppression: - Drugs such as cyclosporine, tacrolimus, sirolimus, mycophenolate, and basiliximab suppress immune responses to prevent rejection.

The Immune System and Cancer

Cancer cells express tumor-associated antigens and are targeted by cytotoxic T lymphocytes (CTLs), activated macrophages, and natural killer (NK) cells. However, cancer cells may evade immune detection by lacking antigenic epitopes, reproducing rapidly, or becoming invisible to the immune system. Immunotherapy includes bacterial endotoxins, vaccines (e.g., HPV, hepatitis B), and monoclonal antibodies.

Immunodeficiencies

Immunodeficiencies are characterized by insufficient immune responses. They may be congenital (genetic defects, e.g., DiGeorge syndrome, SCID) or acquired (e.g., AIDS, caused by HIV infection). AIDS is diagnosed by antibody tests and nucleic acid amplification tests (NAATs), and treated with antiretroviral drugs targeting reverse transcriptase, integrase, and protease enzymes.

Acquired Immunodeficiency Syndrome (AIDS)

HIV infects CD4+ T cells, leading to progressive immune failure. The virus attaches via gp120 to CD4 and CCR5/CXCR4 coreceptors, enters the cell, and integrates its DNA into the host genome. HIV evades immunity by latency, cell-cell fusion, and rapid mutation. The disease progresses through three phases: asymptomatic, symptomatic, and AIDS (CD4+ T cell count < 200/μL). Transmission occurs via blood, semen, breast milk, and other routes. Prevention and treatment include behavioral, biomedical, and structural interventions, as well as antiretroviral therapy.

Summary Table: Types of Hypersensitivity

Type of Reaction	Time Before Clinical Signs	Characteristics	Examples
Type I (Anaphylactic)	< 30 min	IgE binds to mast cells/basophils; allergen binding causes degranulation and release of mediators	Anaphylactic shock, hay fever, asthma
Type II (Cytotoxic)	5-12 hours	IgM/IgG bind to target cell; complement destroys cell	Transfusion reactions, Rh incompatibility
Type III (Immune Complex)	3-8 hours	Antibody-antigen complexes cause inflammation	Arthus reaction, serum sickness, rheumatoid arthritis
Type IV (Delayed Cell-Mediated)	24-48 hours	Antigens activate CTLs that kill target cell	Transplant rejection, contact dermatitis, tuberculosis

Summary Table: Selected Autoimmune Disorders

Autoimmune Disease	Possible Cause
Chronic fatigue syndrome	Antibodies attach to acetylcholine receptors
Rheumatoid arthritis	Immune complexes accumulate in joints
Systemic lupus erythematosus	Immune complexes against DNA
Multiple sclerosis	T cells/macrophages attack myelin sheath
Type 1 diabetes	T cells destroy insulin-secreting cells
Guillain-Barré syndrome	T cells cause destruction of myelin sheath
Psoriasis	T cells induce keratinocyte growth
Graves' disease	Antibodies stimulate thyroid hormone production
Myasthenia gravis	Antibodies block acetylcholine receptors
Crohn's disease	Antibacterial antibodies react with intestinal mucosa
Inflammatory bowel disease	Antibacterial antibodies react with intestinal mucosa

Summary Table: Selected Immunodeficiencies

Disease	Cells Affected	Comments
AIDS	CD4+ T cells	Allows opportunistic infections; caused by HIV
Selective IgA immunodeficiency	B, T cells	Frequent mucosal infections
Common variable hypogammaglobulinemia	B, T cells	Frequent viral/bacterial infections
Reticular dysgenesis	B, T, stem cells	Usually fatal in infancy
SCID	B, T, stem cells	Severe infections; treated with bone marrow transplant
Thymic aplasia (DiGeorge syndrome)	T cells	Absence of cell-mediated immunity; fatal in infancy
Wiskott-Aldrich syndrome	B, T cells	Frequent infections; inherited on X chromosome
X-linked infantile (Bruton’s) agammaglobulinemia	B cells	Frequent bacterial infections; inherited on X chromosome

Summary Table: HIV Life Cycle Drug Targets

Drug Class	Target	Examples
Fusion/Entry Inhibitors	gp41, CCR5	Enfuvirtide, Maraviroc
Reverse Transcriptase Inhibitors	Reverse transcriptase	Tenofovir, Emtricitabine
Integrase Inhibitors	Integrase	Raltegravir, Dolutegravir, Elvitegravir
Protease Inhibitors	Protease	Atazanavir, Indinavir, Saquinavir

Summary Table: Diseases Associated with AIDS

Pathogen/Disease	Disease Description
Cryptosporidium hominis	Persistent diarrhea
Toxoplasma gondii	Encephalitis
Cytomegalovirus (HHV-5)	Fever, encephalitis, blindness
Mycobacterium tuberculosis	Tuberculosis
Pneumocystis jirovecii	Life-threatening pneumonia
Kaposi’s sarcoma	Cancer of skin and blood vessels

Key Terms and Concepts

• Hypersensitivity: Immune response causing undesirable effects.

• Autoimmunity: Loss of self-tolerance; immune response to self-antigens.

• Immunodeficiency: Insufficient immune response; congenital or acquired.

• HLA/MHC: Self-antigens important for tissue matching.

• Antiretroviral Therapy: Drugs targeting HIV enzymes to prevent replication.

Important Equations

• CD4+ T cell count diagnostic for AIDS: $\text{AIDS if CD4^+ T cell count} < 200/\mu L$ *Normal range: 500–1500/μL*

Additional info:

• Stem cell therapy and tissue engineering are emerging fields for transplantation and regenerative medicine.

• Hygiene hypothesis is supported by epidemiological studies comparing urban and rural populations.