Transplantation Immunopathology

Transplantation Immunopathology

• It involves a surgical procedure where tissue or an organ gets transferred from one area of a person's body to another, or from one person (donor) to another (recipient).
• The Major Histocompatibility Complex (MHC) antigens, known as Human Leukocyte Antigen (HLA), are cell surface antigens that decide if transplanted tissue is foreign or not.

Categorization of Transplanted Tissue

• Allogeneic: Donor and recipient are related or unrelated but share similar HLA types.
• Syngeneic: Donor and recipient are identical twins.
• Autologous: Donor and recipient are the same person.

Immune Recognition of Allografts

• Rejection of allografts results from a response to MHC molecules.
• Due to polymorphisms in MHC molecules, no two individuals (except twins) are likely to express the same set of these molecules.
• Allorecognition is defined as the recognition of a foreign antigen by a host.
• There are two main mechanisms through which the host immune system responds to the MHC molecules on the graft.

Direct Recognition

• Host T cells directly recognize the allogeneic (foreign) MHC molecules expressed on graft cells.
• Host CD4+ helper T cells proliferate due to recognizing foreign MHC molecules and produce cytokine, causing delay type hypersensitivity (DTH).
• CD8+ T cells recognize foreign MHC, which kills the cells in the graft.

Indirect Recognition

• Host CD4+ T cells recognize donor MHC molecules after they are processed and presented by the host's antigen-presenting cells.
• Host B cells produce antibodies against graft antigens.

Host-Versus-Graft Disease (HVGD)

• If the transplanted graft bears foreign MHC antigens, the recipient's immune system attacks the donor cells.
• Rejection involves T cell-mediated responses and circulating antibodies.

Types of Transplant Rejection Patterns

• Hyperacute Reaction occurs immediately after transplantation; in kidney transplants, the organ becomes cyanotic and mottled when blood flow from the recipient starts.
• Acute Rejection occurs within the first few months after transplantation and indicates organ failure.
• Chronic HVGD occurs over a long period, manifesting as dense fibrosis of the blood vessels' intimal layer in the transplanted organ.

Graft-Versus-Host Disease (GVHD)

• In GVHD, the transplanted graft's immune system (donor cells) recognizes and attacks the unrelated recipient HLA.
• This primarily occurs in bone marrow transplants, severely immune-compromised patients, and solid organ transplants rich in lymphoid cells like the liver.

Autoimmune Disorders

• Autoimmune disorders result from a breakdown in the immune system's ability to differentiate between self and non-self antigens.
• A high degree of immunologic tolerance to self-antigens normally prevents the immune system from harming the host.

Mechanisms of Autoimmune Disorders

• Opsonization and Phagocytosis: Circulating cells (erythrocytes or platelets) become targets for phagocytosis by neutrophils and macrophages when coated with autoantibodies.
• Inflammation: Antibodies bound to cellular or tissue antigens activate the complement system, triggering inflammation in tissues.
• Antibody-Mediated Cellular Dysfunction: Antibodies directed against cell surface receptors impair or dysregulate cellular function without causing cell injury or inflammation.

Immunologic Tolerance

• Immunologic tolerance is the ability of the immune system to differentiate self from non-self antigens using HLA antigens as recognition markers.
• Autoimmune diseases result from a loss of immune tolerance.

Central Tolerance

• It is the elimination (deletion or death) of auto-reactive T cells in the thymus and B cells in the bone marrow.
• Its deletion is imperfect as lymphocytes may escape into the periphery causing autoimmune diseases.

Peripheral Tolerance

• It is the deletion or inactivation of auto-reactive T or B cells that escaped elimination in the central lymphoid organs.
• Auto-reactive B cells are deleted in the spleen and lymph nodes.
• Auto-reactive T cells may undergo activation, cell death, or become unable to recognize self antigens.

Mechanisms of Tolerance for Auto-Reactive T Cells

• Anergy: functional inactivation of T cells
• Suppression: response regulation of T lymphocytes by regulatory T cells
• Apoptosis: mature lymphocytes undergo programmed cell death due to self-antigen recognition
• Antigen Sequestration: antigens are hidden in immune-privileged sites such as the brain or eye, making it difficult to induce immune responses

Causes of Autoimmune Disease

• Breakdown of self-tolerance links to inheriting susceptibility genes and recognition of self antigens.
• Autoimmune diseases are more likely to occur in families.

Role of Infections and Tissue Injury

• Microbes, including bacteria and viruses, are triggers for autoimmunity.
• Viruses and other microbes, especially streptococci and Klebsiella, may share cross-reacting epitopes with self-antigens, causing the body to attack self-tissues (molecular mimicry).

Examples of Autoimmune Diseases

• Systemic Lupus Erythematosus (SLE); caused by autoantibodies against nuclear antigens, erythrocytes, platelets, and phospholipids with proteins.
• Manifestations include nephritis, skin lesions like a butterfly rash, arthritis, hematologic, and neurologic abnormalities.
• Rheumatoid Arthritis (RA) is a chronic inflammatory disease resulting from an autoimmune response against an unknown self-antigen.
• This leads to T cell reactions in the joint, producing cytokines that activate phagocytes, causing tissue damage (synovitis).
• Sjögren Syndrome is an autoimmune disease with autoantibodies against ductal epithelial cells of exocrine glands, causing dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia).
• It can occur as an isolated disorder (primary form) or in association with other autoimmune diseases, like rheumatoid arthriti
• Morphology:
• Lacrimal and salivary glands are the primary targets.
• Involved tissues show intense lymphocyte (CD4+ T cells) and plasma-cell infiltrate.
• Lacrimal gland destruction results in a lack of tears, resulting in drying of the cornea (keratoconjunctivitis).
• A result of loss of salivary gland output, oral mucosa will show mucosal atrophy (xerostomia).

Immune Deficiencies

• Immune deficiencies are caused by inherited defects affecting the immune system or secondary effects of other diseases.
• Affected patients show greater potential to contract certain infections and forms of cancer.

Types of Immune Deficiency Diseases

• Primary (Congenital): Caused by mutations in genes involved in lymphocyte maturation or function or innate immunity, increasing susceptibility to infections early in life.
• Secondary: More common than primary, and occurs in patients with malnutrition, infection, cancer, renal disease, aging, immunosuppression treatment, autoimmunity, or chemotherapy.

Acquired Immunodeficiency Syndrome (AIDS)

• AIDS is a retroviral illness triggered by the human immunodeficiency virus (HIV), characterized by infection, and depletion of CD4+ T lymphocytes.

Major Routes of HIV infection

• The major routes of HIV infection are:
  • Sexual contact
  • Intravenous drug abuse
  • Transfusion of blood
  • Mothers to their newborn

Pathogenesis of Aids

• HIV infects the immune system
• Primary cellular targets are CD4+ helper T cells that results in T-cell death during viral replication.
• The provirus genome integrates into host cell DNA.
• Viremia includes the dissemination of the virus, resulting in latent infection of the lymphoid tissue.

Clinical Features

• Symptoms of HIV infection range from mild to severe.
• Symptoms include fever, weight loss, diarrhea, lymphadenopathy, infections, neurologic disorders, and secondary neoplasms.