Chapter 19_ImmuneDisorders-AIDS-Cancer

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Autoimmune Diseases

Mechanisms and Types of Autoimmunity

Autoimmune diseases occur when the immune system loses self-tolerance and attacks the body's own tissues. Self-tolerance is the ability of the immune system to distinguish between self and nonself antigens. Autoimmunity can be classified based on the immune mechanisms involved:

Cytotoxic Autoimmune Diseases: Antibodies react with cell-surface antigens, leading to cell damage. Example: Graves’ disease, where abnormal antibodies stimulate the thyroid to produce excess hormones.
Immune Complex Autoimmune Diseases: Immune complexes (antigen-antibody complexes) deposit in tissues, causing inflammation and tissue damage. Examples: Rheumatoid arthritis (joints), systemic lupus erythematosus (kidney glomeruli).
Cell-Mediated Autoimmune Diseases: T cells directly attack body tissues. Examples: Insulin-dependent diabetes mellitus (T cell destruction of pancreatic β-cells), psoriasis, and psoriatic arthritis.

Examples: Arthritis and Autoimmunity

Osteoarthritis: Degenerative joint disease caused by wear and tear; cartilage wears out, leading to bone thickening and restricted movement.
Rheumatoid Arthritis: An autoimmune disease where B cells produce antibodies against proteins in the synovial membrane, causing inflammation, pain, and joint deformities. The disease is intermittent but progressive.

Normal and Arthritic Joints: Comparison of normal, osteoarthritic, and rheumatoid arthritic joints Hand with rheumatoid arthritis showing thickened synovial membrane and degraded cartilage

Risk Factors for Rheumatoid Arthritis

Sex (more common in females)
Age (typically 40-60 years)
Family history
Cigarette smoking
Exposure to asbestos or silica
Obesity (especially in women under 55)
Co-occurrence with anxiety/depression

Reactions Related to the Human Leukocyte Antigen (HLA) Complex

HLA Complex and Disease Susceptibility

The Human Leukocyte Antigen (HLA) complex refers to the major histocompatibility complex (MHC) genes in humans, which encode cell-surface proteins essential for immune recognition. HLA typing is crucial for:

Identifying disease susceptibility (certain HLAs are linked to increased risk of specific diseases)
Transplant surgery (matching donor and recipient tissues)

Table of diseases related to specific HLAs

Transplantation and HLA Matching

Transplants are matched by HLA typing (using antisera, monoclonal antibodies, or PCR) and ABO blood type. If the immune system recognizes the transplant as non-self, rejection occurs. Immunosuppressive drugs are used to prevent rejection.

Tissue typing: serological method for HLA matching

Types of Grafts

Autograft: Tissue from the same individual
Isograft: Tissue from an identical twin
Allograft: Tissue from another person
Xenotransplantation: Tissue from a different species (risk of hyperacute rejection)

Graft-versus-host (GVH) disease can occur when transplanted bone marrow contains immunocompetent cells that attack the recipient.

Immunosuppression in Transplantation

Drugs such as cyclosporine, tacrolimus, sirolimus, mycophenolate, and basiliximab are used to suppress immune responses and prevent transplant rejection.

Privileged Sites and Tissues

Some sites (e.g., cornea, heart valves) are considered immune privileged, meaning transplants in these locations are less likely to be rejected due to limited immune surveillance.

Stem Cells in Transplantation

Stem cells are undifferentiated cells capable of self-renewal and differentiation into specialized cell types. They are used in regenerative medicine and transplantation.

Embryonic stem cells (ESCs): Pluripotent, can generate all cell types; harvested from blastocysts.
Adult stem cells: Found in differentiated tissues; can be reprogrammed to become induced pluripotent stem cells.

Development and differentiation of embryonic stem cells

The Immune System and Cancer

Immune Surveillance and Cancer

The immune system can recognize and destroy cancer cells through immune surveillance. Cancer cells express tumor-associated antigens, which are targeted by cytotoxic T lymphocytes (CTLs) and macrophages. However, some tumors evade immune detection by lacking recognizable antigens, reproducing rapidly, or becoming vascularized.

Cytotoxic T lymphocyte attacking a cancer cell

Immunotherapy for Cancer

Use of immune system components (e.g., monoclonal antibodies, vaccines) to treat or prevent cancer.
Examples: Herceptin® for breast cancer, immunotoxins targeting tumor cells, vaccines for HPV and hepatitis B.
Endotoxins (Coley's toxins) can stimulate immune responses against tumors.

Immunodeficiencies

Types of Immunodeficiencies

Congenital (Primary): Genetic defects leading to missing or defective immune components (e.g., IgA deficiency, severe combined immunodeficiency).
Acquired (Secondary): Develop during life due to infections (e.g., HIV), drugs, or cancers.

Table of immunodeficiencies, affected cells, and comments

Acquired Immunodeficiency Syndrome (AIDS) and HIV

Origin and Transmission of HIV

HIV (Human Immunodeficiency Virus) is a retrovirus that infects CD4+ T helper cells, leading to immune deficiency. It originated from Simian Immunodeficiency Virus (SIV) in primates and crossed into humans in Africa. HIV is transmitted through sexual contact, blood, breast milk, and from mother to child.

Structure and Life Cycle of HIV

HIV is an enveloped virus with single-stranded RNA, reverse transcriptase, and glycoproteins (gp120 and gp41) on its surface.
Attachment: gp120 binds to CD4 receptor and coreceptors (CCR5 or CXCR4) on host cells.
Fusion and Entry: gp41 facilitates fusion; viral RNA enters the cell.
Reverse Transcription: Viral RNA is converted to DNA and integrated into the host genome as a provirus.
Active Infection: New viruses are produced and bud from the cell.
Latent Infection: Provirus remains dormant in host DNA.

HIV structure and attachment to CD4+ T cell HIV attachment, fusion, and entry into CD4+ T cell Latent and active HIV infection in CD4+ T cells

Subtypes and Progression of HIV Infection

HIV-1: Most common, related to viruses in chimpanzees and gorillas.
HIV-2: Less common, related to viruses in monkeys, less pathogenic.

HIV infection progresses through three phases:

Phase 1: Asymptomatic or lymphadenopathy; high viral load.
Phase 2: Decline in CD4+ T cells; mild symptoms (e.g., persistent Candida infections).
Phase 3 (AIDS): CD4+ T cell count below 200 cells/μl; severe opportunistic infections and cancers.

Stages of HIV infection and progression to AIDS Graph of HIV infection progression and CD4+ T cell count

Diagnosis and Epidemiology of HIV/AIDS

Diagnosis: Detection of antibodies (ELISA), viral RNA (APTIMA), or viral proteins (Western blotting). Plasma viral load measured by PCR.
Epidemiology: Over 35 million people infected worldwide; majority of cases in sub-Saharan Africa. Main transmission routes are heterosexual contact, injection drug use, and mother-to-child transmission.

World AIDS Day infographic with global HIV statistics

Prevention and Treatment of HIV/AIDS

Prevention: Safe sex practices, sterile needles, screening blood products.
Treatment: Antiretroviral therapy (ART) includes fusion/entry inhibitors (e.g., enfuvirtide, maraviroc), reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors.
No effective vaccine is currently available due to high mutation rates and lack of natural immunity models.

Drugs that inhibit the HIV life cycle

Additional info:

Some individuals are resistant to HIV infection due to genetic mutations (e.g., CCR5 gene deletion).
Long-term nonprogressors and elite controllers can suppress HIV without progressing to AIDS.