Immunopathology Lecture Notes PDF 2024-2025

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.) Immunologic Tolerance Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen. Self-tolerance refers to lack of responsiveness to an individual’s own antigens, and it underlies our ability to live in harmony with our cells and tissues. ❑T lymphocytes are capable of recognizing an unlimited number of antigens. ❑All immune and blood cells develop from multipotent hematopoietic stem cells that originate in the bone marrow. ❑Exit from BM, immature T cells undergo final maturation process in the Thymus that "educates" them to distinguish between self and non-self antigens. ❑ In normal persons, the autoreactive T- cells are deleted or inactivated. Mechanisms of self-tolerance The mechanisms of self-tolerance can be broadly classified into two groups: Central tolerance: Immature lymphocytes that recognize self antigens in the central (generative) lymphoid organs are killed by apoptosis. These organs are thymus for T cells and the bone marrow for B cells. Peripheral tolerance: Self-reactive lymphocytes that escape negative selection can inflict tissue injury unless they are deleted in the peripheral tissues by 3 mechanisms: ❖Anergy : irreversible inactivation ( rather than apoptosis) of lymphocytes. Mature lymphocytes that recognize self antigens in peripheral tissues become functionally inactive (anergic). ❖Suppression by regulatory T cells. A population of T cells called regulatory T cells functions to prevent immune reactions against self antigens. ❖Deletion by apoptosis. T cells that recognize self antigens may receive signals that promote their death by apoptosis Autoimmune Diseases Autoimmune diseases arise when the induction and maintenance of immune tolerance fails. So here our immune system will attack self antigens. These diseases result in cell and tissue destruction by: 1- antigen-specific CD8 cytotoxic T cells or 2- autoantibodies (antibodies to self-proteins) and the accompanying inflammatory process.  Causes of Autoimmune Diseases Exact reasons are unclear. However ; Genetics along with environmental factors (like hormonal influences, chemical, physical, and certain infections) may contribute to the tolerance failure & development of autoimmune diseases Role of Susceptibility Genes Most autoimmune diseases are complex multigenic disorders. It has been known for decades that autoimmunity has a genetic component. The incidence of many autoimmune diseases is greater in twins of affected individuals than in the general population, and greater in monozygotic than in dizygotic twins. A proof that genetics contributes to the development of these disorders. The most striking of these associations is between ankylosing spondylitis and HLA-B27. Role of Infections and Other Environmental Factors Autoimmune reactions may be triggered by infections by following mechanisms: 1- infections may upregulate the expression of costimulators on APCs. If these cells are presenting self antigens, the result may be a breakdown of anergy and activation of T cells specific for the self antigens. 2- some microbes may express antigens that share amino acid sequences with self antigens. Immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes. This phenomenon is called molecular mimicry. A clear example of such mimicry is rheumatic heart disease, in which antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis. 3- Microbes may induce other abnormalities that promote autoimmune reactions. Some viruses, such as EBV and HIV, cause polyclonal B-cell activation, which may result in production of autoantibodies. 4-Modification in the structure of self antigen so became as a foreign antigen by T cells. e.g. smoking induce chemical modification of self Ag. As in RA 5. Release of sequestered antigens: Any self antigen that is completely sequestered (hidden) from the immune system during development is likely to be recognized as foreign antigen if it is subsequently exposed to the immune system. e.g. ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens, which elicit pathologic immune responses in lupus. 6. Finally, there is a strong gender bias of autoimmunity, with many of these diseases being more common in women than in men. The underlying mechanisms are not well understood, but may involve the effects of hormones and other factors. Examples of Autoimmune Diseases ❑Organ specific autoimmune disorders ▪ Type I diabetes mellitus ▪ Pernicious anemia ▪ Gravis disease ▪ Hypothyroidism ▪ Autoimmune hepatitis and primary biliary cirrhosis ▪ Sjögren syndrome Multisystem autoimmune diseases ▪ Rheumatoid arthritis ▪ Systemic lupus erythematosus (SLE) ▪ Polyarteritis nodosa ▪ Auto immune hemolytic anemia ▪ Systemic Sclerosis (Scleroderma)  Sjögren syndrome Sjögren syndrome is a chronic autoimmune inflammatory disease that affects primarily the salivary and lacrimal glands, causing dryness of the mouth(xerostomia) and eyes(xerophthalmia). Pathogenesis: Multifactorial ❑The initiating trigger may be a viral infection of the salivary glands, which causes local cell death and release of tissue self antigens. ❑In genetically susceptible individuals, CD4+ T cells and B cells specific for these self antigens may have escaped tolerance and are able to react. ❑antibodies directed against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La) which can be detected in as many as 90% of patients by sensitive techniques. ❑The result will be inflammation, tissue damage and eventually, fibrosis. The characteristic decrease in tears and saliva (sicca syndrome) is the result of lymphocytic infiltration and fibrosis of the lacrimal and salivary glands. ❑ The infiltrate contains predominantly activated CD4+ helper T cells and some B cells, including plasma cells. Morphology ❖The earliest histologic finding in involved salivary glands is periductal and perivascular lymphocytic infiltration. ❖Eventually the lymphocytic infiltrate becomes extensive, and lymphoid follicles with germinal centers may appear. ❖The ductal lining epithelial cells may show hyperplasia, thus obstructing the ducts. ❖Later there is atrophy of the acini, fibrosis, and hyalinization. ❖ later in the course, atrophy and replacement of parenchyma with fat (A)Enlargement of the salivary gland. (B) Intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia in a salivary gland Clinical Features ❖Sjögren syndrome occurs most commonly in women between 50 and 60 years of age. ❖ As might be expected, symptoms result from inflammatory destruction of the exocrine glands. ❖The keratoconjunctivitis produces blurring of vision, burning, and itching, and thick secretions accumulate in the conjunctival sac. ❖ The xerostomia results in difficulty in swallowing solid foods, a decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa. ❖Parotid gland enlargement is present in one-half of patients. ❖dryness of the nasal mucosa, epistaxis, recurrent bronchitis, and pneumonitis are other symptoms. ❖Extraglandular manifestations are seen in one-third of patients and include: ❑ synovitis ❑ diffuse pulmonary fibrosis ❑ peripheral Neuropathy ❖The combination of lacrimal and salivary gland inflammation is called Mikulicz syndrome. ❖ there is a strong tendency over time for individual for the development of a marginal zone lymphoma, a specific type of B-cell malignancy Sjogren syndrome may be associated with  Systemic Sclerosis (Scleroderma) Systemic sclerosis is an immunologic disorder characterized by excessive fibrosis in multiple tissues, obliterative vascular disease, and evidence of autoimmunity, mainly the production of multiple autoantibodies. Systemic sclerosis is classified into two groups on the basis of its course: ❑ Diffuse systemic sclerosis, characterized by initial widespread skin involvement, with rapid progression and early visceral involvement ❑ Limited systemic sclerosis, with relatively mild skin involvement, often confined to the fingers and face. Involvement of the viscera occurs late, so the disease generally follows a fairly benign course. This presentation also is called CREST syndrome because of its frequent features of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. Pathogenesis The cause of systemic sclerosis is not known, but the disease likely results from three interrelated processes— autoimmune responses, vascular damage, and collagen deposition. Autoimmunity. It is proposed that CD4+ T cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that activate inflammatory cells and fibroblasts. Vascular damage. Microvascular disease is consistently present early in the course of systemic sclerosis. signs of endothelial activation and injury and increased platelet activation have been noted. However, the cause of the vascular injury is not known; it could be the initiating event or the result of chronic inflammation, with mediators released by inflammatory cells inflicting damage on microvascular endothelium. Eventually, widespread narrowing of the microvasculature leads to ischemic injury and scarring. The pulmonary vasculature is frequently involved, and the resulting pulmonary hypertension is a serious complication of the disease.  Fibrosis. The progressive fibrosis characteristic of the disease may be the culmination of multiple abnormalities, including the accumulation of alternatively activated macrophages, actions of fibrogenic cytokines produced by infiltrating leukocytes, hyperresponsiveness of fibroblasts to these cytokines, and scarring following ischemic damage caused by the vascular lesions.  Pathogenesis of systemic sclerosis organs pDCs, plasmacytoid dendritic cells; DCs, dendritic cells; TGF-β, transforming growth factor-β; Th, T helper; EndoMT, endothelial-to-mesenchymal transition;EMT, epithelial-to-mesenchymal transition; AMT, adipocyte-to-myofibroblast transdifferentiation*. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565034 / MORPHOLOGY In systemic sclerosis, the most prominent changes occur in the skin, alimentary tract, musculoskeletal system, and kidney, but lesions also are often present in the blood vessels, heart, lungs, and peripheral nerves. Skin. Most patients have diffuse fibrosis of the skin and associated atrophy, which usually begins in the fingers and distal regions of the upper extremities and extends proximally to involve the upper arms, shoulders, neck, and face.. In advanced stages the fingers take on a tapered, clawlike appearance and have limited joint mobility, and the face becomes a drawn mask. Loss of blood supply may lead to cutaneous ulcerations and atrophic changes or even autoamputation of the terminal phalanges. Alimentary Tract. The alimentary tract is affected in approximately 90% of patients. Progressive atrophy and fibrous replacement of the muscularis may develop at any level of the gut but are most severe in the esophagus causing stricture. Fibrosis in the small intestine cause malabsorption. Musculoskeletal System. Inflammation of the synovium, associated with synoviocyte hypertrophy, is common in the early stages; fibrosis later ensues. Kidneys. Renal abnormalities occur in two-thirds of patients. The most prominent are the vascular lesions. Including intimal thickening resemble those seen in malignant hypertension. There are no specific glomerular changes. Lungs. The lungs are affected in more than 50% of cases. This involvement may manifest as pulmonary hypertension and interstitial fibrosis. Heart. Pericarditis with effusion, myocardial fibrosis. Systemic Sclerosis of the Hand Systemic Sclerosis Applications of immunity in clinical practice ❖https://scholar.google.com/citations?view_op=view_citation&hl=ar&user =H8_bMaEAAAAJ&citation_for_view=H8_bMaEAAAAJ:Tyk- 4Ss8FVUC ❖https://www.yalemedicine.org/news/how-immunotherapy-can-treat- cancer-and-autoimmune-diseases