Transplantation Immunopathology

Transplantation Immunopathology

• Transplantation is a surgical procedure where tissue or an organ is transferred from one area of a person's body to another, or from a donor to a recipient.
• The major histocompatibility complex (MHC) antigens, also known as human leukocyte antigens (HLA), play a key role in determining whether transplanted tissue is recognized as foreign.

Types of Transplanted Tissue

• Allogeneic: Tissue from a donor and recipient who are related or unrelated but share similar HLA types.
• Syngeneic: Tissue from a donor and recipient who are identical twins.
• Autologous: Tissue from a donor and recipient who are the same person.

Immune Recognition of Allografts

• Rejection of allografts occurs due to the response to MHC molecules.
• MHC molecules are highly polymorphic. This makes it unlikely for two unrelated individuals to express the same set of MHC molecules.
• Allorecognition involves a host recognizing a foreign antigen.
• There are two main mechanisms by which a host immune system recognizes and responds to MHC molecules on a graft.

Direct Recognition

• Host T cells directly recognize allogeneic (foreign) MHC molecules expressed on graft cells.
• Host CD4+ helper T cells are triggered into proliferation upon recognizing foreign MHC molecules.
• This proliferation leads to cytokine production, causing delayed type hypersensitivity.
• CD8+ T cells recognize foreign MHC. This leads to the cells in the graft being killed.

Indirect Recognition

• Host CD4+ T cells recognize donor MHC molecules which are picked up, processed, and presented by the host's antigen-presenting cells.
• Production of antibodies by host B cells against graft antigens.

Host-Versus-Graft Disease (HVGD)

• HVGD occurs when the recipient's immune system attacks the donor cells of the transplanted organ, due to foreign MHC antigens.
• Rejection involves T cell-mediated responses and circulating antibodies.
• There are three basic patterns of transplant rejection.

Types of Transplant Rejection

• Hyperacute reaction: Occurs immediately after transplantation, resulting in a cyanotic, mottled appearance of the donor organ, typically in kidney transplants.
• Acute rejection: Occurs within the first few months after transplantation, evidenced by signs of organ failure.
• Chronic HVGD: Occurs over a prolonged period, characterized by dense fibrosis of the intimal layer of blood vessels in the transplanted organ.

Graft-Versus-Host Disease (GVHD)

• GVHD involves the cellular immune system of the transplanted graft (donor cells) recognizing and attacking the unrelated recipient HLA.
• GVHD mainly occurs in bone marrow transplants, severely immune-compromised patients, and after transplantation of solid organs rich in lymphoid cells, such as the liver.

Autoimmune Disorders

• Autoimmune disorders arise from a breakdown in the immune system's ability to differentiate between self and non-self antigens.
• Normally, there is a high degree of immunologic tolerance to self-antigens, preventing the immune system from destroying the host.

Mechanisms of Autoimmunity

• Opsonization and phagocytosis: Circulating cells, such as erythrocytes or platelets, are coated (opsonized) with autoantibodies, making them targets for phagocytosis by neutrophils and macrophages.
• 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.
  • Myasthenia Gravis: Antibodies against acetylcholine receptors inhibit neuromuscular transmission, leading to muscle weakness.
  • Graces' disease: Antibodies stimulate thyroid epithelial cells to secrete thyroid hormones, causing hyperthyroidism.

Immunologic Tolerance

• Immunologic tolerance is the ability of the immune system to differentiate self from non-self antigens through HLA antigens, serving as recognition markers. Autoimmune diseases occur due to a loss of immune tolerance.
• Central tolerance: It involves the elimination or death of auto-reactive T cells in the thymus and B cells in the bone marrow.
• Peripheral tolerance: It involves the deletion or inactivation of auto-reactive T cells 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, induced cell death, or be rendered inactive to prevent recognition of self-antigens.

Mechanisms of Tolerance for Auto-Reactive T Cells

• Anergy: Functional inactivation of T cells.
• Suppression of T lymphocyte responses by regulatory T cells.
• Apoptosis (programmed cell death) of mature lymphocytes due to self-antigen recognition.
• Antigen sequestration: Some antigens are hidden from the immune system in immune-privileged sites, such as the brain and eye, thus limiting immune responses.

Causes of Autoimmune Disease

• Autoimmune break down of self-tolerance and autoimmunity development relate to the inheritance of susceptibility genes, changes in tissues, and recognition of self-antigens.
• Genetic factors: Autoimmune diseases tend to run in families.

Role of Infections and Tissue Injury

• Microbes and viruses can trigger autoimmunity.
• Viruses and microbes, particularly certain bacteria like streptococci and Klebsiella, may share cross-reacting epitopes with self-antigens.
• The body's responses to microbial antigens may attack self-tissues. This is known as molecular mimicry.
• Molecular mimicry can cause rheumatic heart disease, where an immune response against streptococci cross-reacts with cardiac antigens.

Examples of Autoimmune Diseases

• SLE is caused by autoantibodies directed against nuclear antigens, erythrocytes, platelets, and phospholipid complexes with proteins. The manifestations include nephritis, skin lesions like "butterfly" rash, arthritis, and hematologic/neurologic abnormalities.
• RA: Chronic inflammatory disease caused by an autoimmune response against an unknown self-antigen, leading to T cell reactions in the joint. This causes the production of cytokines that activate phagocytes to damage tissues (synovitis).
• Sjogren Syndrome: Autoimmune disease with autoantibodies against ductal epithelial cells of exocrine glands, causing dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) due to destruction of lacrimal and salivary.
  • Isolated disorder (primary form) is also known as sicca syndrome.
  • Secondary form is associated with another autoimmune disease, commonly rheumatoid arthritis.
• Morphology of Sjögren's syndrome includes lacrimal and salivary glands as primary targets; intense lymphocyte (CD4+ T cells) and plasma-cell infiltrate in involved tissues; lacrimal gland destruction leading to drying of the corneal (keratoconjunctivitis); mucosal atrophy due to the loss of salivary gland ouput; and dryness and crusting of the nose may cause ulcerations.

Immune Deficiencies

• Immune deficiencies are caused by inherited defects affecting the immune system, developmental issues, or secondary effects of other diseases.
• Patients present with increased susceptibility to infections and certain forms of cancer.
• There are two types of immune deficiency diseases, primary and secondary.

Primary (congenital) Immune Deficiencies

• caused by mutations in genes involved in lymphocyte maturation, function, or in innate immunity.
• They have increased susceptibility to infections in early life

Secondary Immune Deficiencies

• Secondary immune deficiencies are more common than primary.
• They occur in patients with malnutrition, infection, cancer, renal disease, aging, immunosuppression treatment, autoimmunity, or chemotherapy.

Acquired Immunodeficiency Syndrome (AIDS)

• AIDS is a retroviral disease caused by the human immunodeficiency virus (HIV).
• It is characterized by infection and depletion of CD4+ T lymphocytes.
• The major routes of HIV infection are sexual contact, intravenous drug use, blood transfusions, and transmission from infected mothers to newborns.

Pathogenesis of AIDS

• The two major targets of HIV infection are the immune system and the central nervous system (CNS).
• Virus entry into cells involves CD4+ helper T cells as the main cellular targets, leading to T-cell death during viral replication.
• During viral replication, the provirus genome integrates into the host cell DNA.
• Progression of infection causes viremia with dissemination of the virus, latent infection of cells in lymphoid tissue, continued viral replication, and progressive loss of CD4+ T cells.

Clinical Features of AIDS

• The clinical manifestations of HIV infection range from a mild acute illness to severe disease.
• Patients typically present with fever, weight loss, diarrhea, generalized lymphadenopathy, multiple infections, neurologic disease, and secondary neoplasms.