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**I. Diseases of the Immune System**

This lecture covers three main categories of immune system diseases: Hypersensitivity reactions (briefly mentioned, not elaborated on), Transplantation Immunopathology, and Autoimmune Disorders.

**II. Transplantation Immunopathology**

This section focuses on the immune system's response to transplanted organs and tissues.

*   **A. Introduction to Transplantation:**
    *   Transplantation of solid organs and bone marrow is now commonplace.
    *   Success depends on understanding immune responses and using immunosuppressive drugs (like cyclosporine).
    *   A critical factor is the Major Histocompatibility Complex (MHC), also known as Human Leukocyte Antigen (HLA), which are cell surface antigens that determine whether transplanted tissue is recognized as foreign.

*   **B. Types of Transplanted Tissue (Grafts):**
    1.  **Allogeneic:** Donor and recipient are related or unrelated but share similar HLA types.
    2.  **Syngeneic:** Donor and recipient are identical twins.
    3.  **Autologous:** Donor and recipient are the same person (e.g., skin grafts from one part of the body to another).

*   **C. Immune Recognition of Allografts:**
    *   Rejection is primarily a response to MHC molecules, which are highly polymorphic (vary greatly between individuals).
    *   There are two main recognition mechanisms:
        1.  **Direct Recognition:** Host T cells directly recognize foreign MHC molecules on graft cells.
            *   Graft DCs (dendritic cells) are the most likely APCs in direct recognition because they express high levels of MHC.
            *   Host CD4+ helper T cells are triggered, leading to proliferation, cytokine production, and a **delayed-type hypersensitivity (DTH)** reaction.
            *   CD8+ T cells differentiate into cytotoxic T cells (CTLs) that kill graft cells.
        2.  **Indirect Recognition:** Host immune cells process and present donor MHC molecules to host T cells.
            *   Host CD4+ T cells recognize donor MHC molecules after they are processed and presented by host APCs, triggering a DTH reaction.
            *   Host B cells produce antibodies against graft alloantigens, stimulated by Helper T cells.

*   **D. Host-Versus-Graft Disease (HVGD) / Transplant Rejection:**
    *   The recipient's immune system attacks the donor cells of the transplanted organ.
    *   Rejection involves both T cell-mediated and antibody-mediated responses.
    *   Recipient antibodies initially target the graft vasculature (blood vessels).
    *   **Patterns of Transplant Rejection:**
        1.  **Hyperacute Rejection:** Occurs immediately after transplantation, caused by pre-existing antibodies against the donor's antigens. In kidney transplants, the organ becomes cyanotic and mottled as blood flow begins.
        2.  **Acute Rejection:** Usually occurs within the first few months after transplantation and is characterized by signs of organ failure. It's mediated by both T cells and antibodies.
        3.  **Chronic Rejection:** Occurs over a prolonged period, leading to dense fibrosis (scarring) of the intimal layer of blood vessels in the transplanted organ.

*   **E. Graft-Versus-Host Disease (GVHD):**
    *   The cellular immune system of the transplanted graft (donor T cells) attacks the recipient's HLA.
    *   Primarily occurs in:
        1.  Bone marrow transplantation.
        2.  Severely immunocompromised patients who receive blood products with HLA-incompatible lymphocytes.
        3.  After transplantation of solid organs rich in lymphoid cells (e.g., liver).

**III. Autoimmune Disorders**

This section discusses diseases where the immune system attacks the body's own tissues.

*   **A. Introduction to Autoimmune Disorders:**
    *   Caused by a breakdown in the ability of the immune system to differentiate between self and non-self antigens.
    *   Normally, there is a high degree of immunologic tolerance to self-antigens.
    *   Autoimmune diseases can affect almost any cell or tissue.
    *   Some disorders are tissue-specific (e.g., affecting only the thyroid), while others affect multiple organs and systems (systemic).

*   **B. Mechanisms of Antibody-Mediated Diseases (Type II Hypersensitivity):**
    1.  **Opsonization and Phagocytosis:** Autoantibodies coat cells (like red blood cells or platelets), making them targets for phagocytosis by macrophages and neutrophils.
        *   This process often occurs in the spleen, and splenectomy (removal of the spleen) can be a treatment option for some autoimmune conditions.
    2.  **Inflammation:** Antibodies bound to cellular or tissue antigens activate the complement system, which recruits inflammatory cells (neutrophils, monocytes), triggers inflammation, opsonizes cells, and can lead to cell lysis.
    3.  **Antibody-Mediated Cellular Dysfunction:** Antibodies can disrupt or dysregulate cell function without causing direct cell injury or inflammation.
        *   **Examples:**
            *   **Myasthenia Gravis:** Antibodies against acetylcholine receptors impair neuromuscular transmission, leading to muscle weakness.
            *   **Graves' Disease:** Antibodies against the thyroid-stimulating hormone (TSH) receptor stimulate thyroid hormone production, causing hyperthyroidism.

*   **C. Immunologic Tolerance: Self-Tolerance:**
    *   The ability of the immune system to distinguish self from non-self antigens, based on the presence of HLA antigens.
    *   Autoimmune diseases result from a loss of this immune tolerance.
    *   **Mechanisms of Self-Tolerance:**
        1.  **Central Tolerance:** Elimination (deletion or death) of autoreactive T cells in the thymus and B cells in the bone marrow.
            *   Clonal deletion is not perfect; some autoreactive lymphocytes escape into the periphery.
        2.  **Peripheral Tolerance:** Deletion or inactivation of autoreactive T cells or B cells that escaped central tolerance.
            *   Autoreactive B cells are deleted in the spleen and lymph nodes.
            *   Autoreactive T cells may undergo activation, induced cell death, or be rendered inactive.
        3.  **Mechanisms in Peripheral Tissues that Silence Autoreactive T Cells:**
            *   **Anergy:** Functional inactivation of lymphocytes.
            *   **Suppression by Regulatory T cells:** Regulatory T cells suppress the response of other T lymphocytes.
            *   **Activation-Induced Cell Death:** Apoptosis (programmed cell death) of mature lymphocytes upon self-antigen recognition.
            *   **Antigen Sequestration:** Some antigens are hidden from the immune system because the tissues containing them don't communicate with blood and lymph (immune-privileged sites, e.g., the eye, brain).


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