Immunopathology Lecture Notes 2024-2025 PDF

Nineveh university - College of medicine Immunopathology 2024-2025 Dr. Hadeel. T. Ali. AL-Obaidy College of medicine, Nineveh university M.B.Ch.B, MS...

Nineveh university - College of medicine Immunopathology 2024-2025 Dr. Hadeel. T. Ali. AL-Obaidy College of medicine, Nineveh university M.B.Ch.B, MSc., (Path.) C.A.B. (Path.)  Tissue Transplantation Grafts are divided into 4 types The graft contains: ❑ Tissues of the organ (MHC) ❑ Some lymphocytes of the donor ❑ Some macrophage (APC) of the donor Problems of Transplantation 1- Graft rejection (Host versus graft) 2- Graft versus host reaction (GVH)  Graft Rejection Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and destroy tissue grafts. ❑It is a complex immunologic phenomenon as responses of the host directed against MHC on the donor graft. ❑The rejection happens because the MHC (HLA) system of the donor is different from that of the recipient so that both cell mediated immunity and antibody response will be mounted against the transplanted tissue. ❑The major types of hypersensitivity reactions involved are types II, III and IV. Kidney is the most common transplanted organ MECHANISMS OF GRAFT REJECTION 1. CELLULAR REACTIONS : These are mainly responsible for graft rejection and are mediated by T cells. 2. HUMORAL REACTIONS : These include: preformed circulating antibodies due to pre- sensitisation of the recipient before transplantation e.g. by blood transfusions and previous pregnancies.  Pathology, types of graft rejection(renal) 1-Hyperacute rejection: Pre-formed antidonor antibodies bind to graft endothelium immediately after transplantation. This occurs due to previous sensitization by previous transplantation or blood transfusion In the transplanted kidney the surgeon will notice, (just after vascular anastomosis), that the kidney will become cyanosed and secretes only few drops of bloody urine. Microscopically, arterioles and arteries exhibit acute fibrinoid necrosis of their walls (vasculitis) and narrowing or complete occlusion of their lumens by thrombi. Affected kidneys are nonfunctional and have to be removed 2-Acute rejection: This occurs few days after transplantation or after stoppage of the immunosuppressive therapy. ❑Acute cellular rejection: T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions. ❑ Acute humoral rejection: Antibodies damage graft vasculature. Microscopically: Cellular rejection is manifested by extensive interstitial mononuclear cell infiltrate. Humoral rejection is manifested by acute necrotizing vasculitis leading to narrowing of renal arterioles and infarction of renal cortex.  3-Chronic rejection: ▪ Occurs months-years after transplantation. ▪ This type is probably caused by T cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis. ▪ Microscopically: ▪ vasculitis with marked thickening of intima (intimal fibrosis) leading to obliteration of vessel lumen and renal ischemia with fibrosis of glomeruli, interstitial fibrosis and atrophy of tubules. Methods of increasing graft survival 1- The best results will be obtained from finding of HLA compatible donor but unfortunately this is not available except from an identical twin and 1:4 of brothers or sisters. 2- When the donor is not compatible immunosuppression like high doses of prednisolone or cytotoxic therapy. Both cause non-specific immunosuppression and the patient may suffer from opportunistic infections. 3- Now a days, antithymocytes antibodies are used. 4- Repeated blood transfusion in small doses from the same donor before transplantation increases the success of kidney transplantation. Graft Versus Host Disease (GVHD) occurs when immunologically competent cells or their precursors are transplanted into immunologically compromised recipients, and the transferred cells recognize alloantigens in the host and attack host tissues. It mat be : Acute or Chronic  It is seen most commonly in the setting of HSC(BM) transplantation but, rarely may occur following transplantation of solid organs rich in lymphoid cells (e.g., the liver). When immune-compromised recipients receive HSC preparations from allogeneic donors, the immunocompetent T cells present in the donor tissue recognize the recipient’s HLA antigens as foreign and react against them. Both CD4+ and CD8+T cells recognize and attack host tissues by generating DTH and cell mediated cytotoxicity ❑The main cells involved in GVHD are CD8+ T-lymphocytes. ❑The donor cells will attack the actively proliferating cells of the recipient resulting in gastroenteritis (nausea & vomiting), skin rash, jaundice, etc… ❑Mainly occurs in bone marrow transplantation. ❑Before transplantation, we should destroy all the recipient marrow by total body irradiation and cytotoxic drugs, and this will make the patient (recipient) immunodeficient. ❑After that the new bone marrow is transplanted, its cytotoxic T- lymphocytes will attack the recipient tissues.  GVHD is a lethal and can be minimized by: Proper HLA typing Donor T cells can be depleted before marrow transplantation. IMMUNODEFICIENCY SYNDROMES are characterized by deficient or absent cellular and/or humoral immune functions. Clinically patients with immune deficiency present with increased susceptibility to infections as well as to certain forms of cancer.  Classification of Primary immunodeficiency B-cell deficiencies: ○ X-linked agammaglobulinemia (Bruton type) ○ Common variable immunodeficiency ○ Isolated IgA deficiency T-cell deficiencies: ○ Hyper-IgM syndrome ○ DiGeorge syndrome o Severe combined immunodeficiency complement system deficiencies: phagocytic system deficiencies: occur when there is defect in any one of many steps involved in lymphocyte development Severe combined immunodeficiency (SCID) ❑Prominent susceptibility to severe, recurrent fungal (Candida albicans), viral, and bacterial infections ❑ Both humoral (antibodies) and cellular (T cells) immune responses severely reduced Despite the common clinical manifestations, the underlying genetic defects are quite varied and in many cases are unknown X-linked SCID. The most common form, 50% to 60% of cases, is X-linked,. X- chromosome linked (boys are typically affected); mutation involves the gene encoding cytokine receptors Autosomal Recessive SCID. The remaining forms of SCID are autosomal recessive disorders. The most common cause of autosomal recessive SCID is a deficiency of the enzyme adenosine deaminase (ADA) DiGeorge syndrome ❑ T-cell deficiency due to the abnormal development of thymus (hypoplasia or lack of the thymus), ❑ Part of CATCH 22 syndrome: cardiac abnormality, Abnormal facies , Thymic aplasia, cleft palate, hypocalcemia; ❑syndrome is caused by a chromosome 22q11 deletion X-linked agammaglobulinemia ( Bruton) ❑Failure of B-cell precursors (pro-B cells and pre-B cells) to mature into B cells due to mutation of B-cell tyrosine kinase (Btk). ❑B cells are absent or markedly decreased in the circulation. ❑Absent or markedly decreased concentration of all classes of immunoglobulins (agammaglobulinemia) ❑ Affects boys (X-linked disease) ❑Symptoms appear after 6 months of age. Typically, there is an increased incidence of otitis media, and skin and respiratory infections caused by Streptococcus pneumoniae, or Staphylococcus aureus. These organisms are normally opsonized by antibodies and cleared by phagocytosis Common variable immunodeficiency ❑ Most patients have normal or near-normal numbers of B cells in the blood and lymphoid tissues which are not able to differentiate into plasma cells. ❑Late-childhood onset of hypogammaglobulinemia and recurrent infections ❑Boys and girls affected equally ❑ High frequency of malignancies (gastric cancer and lymphoma) later in life ❑Isolated IgA immunodeficiency ❑ The most common congenital immunodeficiency, found in 1:850 people. caused by impaired differentiation of naïve B lymphocytes to IgA-producing plasma cells. ❑Many of these men and women are asymptomatic. ❑Because IgA is the major immunoglobulin found in mucosal secretions (respiratory, gastrointestinal, and urogenital tract), IgA deficiency is characterized by recurrent sinusitis, pulmonary and urinary infections, as well as recurrent diarrhea. ❑In addition, IgA-deficient patients have a high frequency of respiratory tract allergy and a variety of autoimmune diseases, particularly SLE and rheumatoid arthritis  X-linked hyper-IgM syndrome Affected people have high titers of IgM and IgD antibodies but low titers of IgG, IgA, and IgE antibodies, indicating that there is a defect in isotype switching. ❑The primary defect is in CD4 T cells, which are responsible for production of cofactors necessary for stimulation of B-cell and isotype switching. ❑The cause is a mutation of X-chromosome gene encoding CD40L. This protein expressed on CD4 lymphocytes acts as a ligand binding to a B-cell surface receptor (CD40). Binding of this ligand is important for the activation of B cells. ❑Patients suffer from pyogenic infections and are susceptible to infection with Pneumocystis jiroveci.  Chediak- Higashi syndrome ❑This syndrome is marked by reduced( slower rate) of intracellular killing and chemotactic movement accompanied by inability of phagosome-lysosome fusion and proteinase deficiency. ❑Associated with NK cell defect, platelet and neurological disorders Secondary immunodeficiency Secondary immunodeficiency are more common than primary, main causes are: 1. Malnutrition 2. Diabetes and other metabolic diseases 3. Infection e.g. HIV/AIDS 4. Cancer 5. Renal diseases 6. Patients receiving chemotherapy or radiotherapy for treatment of cancer 7. Use of immunosuppressive therapy to prevent graft rejection AIDS Definition: infectious disease caused by human immunodeficiency viruses (HIV) characterized by immunosuppression associated with the triad of opportunistic infections, secondary neoplasms and neurologic manifestations.  AIDS-Defining lesions in Patient with HIV-Infection: 1- Opportunistic infections in AIDS Opportunistic infections account for the vast majority of deaths in patients. These infections include: 1. Pneumocystis jiroveci pneumonia 2. Candida albicans infections of the mouth, esophagus, vagina, and lungs 3. Cytomegalovirus enteritis and pneumonitis 4. Atypical mycobacterial infection (M. avium-intracellulare) of the gastrointestinal tract 5. Cryptococcus neoformans meningitis 6. Cryptosporidium enteritis 2- The most common neoplasms associated with HIV infections 1. Kaposi sarcoma 2. Non-Hodgkin lymphoma 3. Carcinoma of the uterine cervix 4. Squamous cell carcinoma of the skin Kaposi sarcoma : atypical spindle cells enclosing slit like vascular spaces this rare tumor is a frequent finding in patient with AIDS.