IMMUNOGENETICS GENETIC DISORDERS OF THE IMMUNE SYSTEM

1. IMMUNOGENETICS • GENETIC DISORDERS OF THE IMMUNE SYSTEM

2. Genetic Mutations: acquired and germline. • Acquired mutations are the most common cause of cancer. These mutations occur from damage to genes during a person’s life, and they are not passed from parent to child. Tobacco use, exposure to ultraviolet (UV) radiation), viruses, and age can damage genes and cause these mutations. • Cancer that occurs because of acquired mutations is called sporadic cancer. • Cancer caused by germline mutations is called inherited cancer, which makes up about 5% to 10% of all cancers.

3. MUTATIONS AND CANCER Mutations happen often, and the human body is normally able to correct most of these changes. Depending on where in the gene the change occurs, a mutation may be beneficial, harmful, or make no difference at all. Therefore, the likelihood of one mutation leading to cancer is small. Usually, it takes multiple mutations over a lifetime to cause cancer. This is why cancer occurs more often in older people, for whom there have been more opportunities for mutations to build up.

4. TYPES OF GENES LINKED TO CANCER Tumor suppressor genes are protective genes. BRCA1, BRCA2, and p53 are examples of tumor suppressor genes. Germline mutations in BRCA1 or BRCA2genes increase a woman’s risk of developing hereditary breast or ovarian cancers. The most commonly mutated gene in people who have cancer is p53. In fact, more than 50% of all cancers involve a missing or damaged p53 gene. Most p53 gene mutations are acquired mutations. Germlinep53 mutations are rare. Oncogenes turn a healthy cell into a cancerous cell. HER2 (a specialized protein that controls cancer growth and spread, found on some cancer cells, such as breast and ovarian cancer cells) and the ras family of genes (genes that make proteins involved in cell communication pathways, cell growth, and cell death) are common oncogenes. Mutations in these genes are almost always acquired (not inherited). DNA repair genes fix mistakes especially if the mutation occurs in a tumor suppressor gene or oncogene. Mutations in DNA repair genes can be inherited or acquired. 

5. Despite all that is known about the different ways cancer genes work, many cancers cannot be linked to a specific gene. It is likely that multiple, different genes are involved in the development of cancer. There is also some evidence that genes interact with their environment, further complicating the role of genes in cancer.

6. CAUSES DNA DAMAGE

8. IMMUNODEFICIENCY impaired function of the immune system (immunodeficiency) resulting in increased susceptibility to infection. Primary immunodeficiency-PID intrinsic defect of a component of the immuneMost by defects in single genes and are hence heritable.. rare Secondary or acquired secondary to another pathological condition, which adversely affects immune function,

11. From a clinical perspective, immuno- deficiencies can be classified into eight categories

12. DEFECTS IN ANATOMICALOR PHYSIOLOGICAL BARRIERS TO INFECTION • integumentary damage caused by burns, eczema, and trauma (including surgery) • Skull fractures, particularly damage of the cribriform plate, ….recurrent episodes of pyogenic meningitis. • Existence of sinus tracts between deeper tissues and the skin surface or alternatively, the presence of foreign bodies or avascular areas (e.g., within bone) • Obstruction to the drainage of hollow tubes and viscera also predisposes to infection, for example, obstruction of the biliary tract, urinary tract, or bronchi. • Impaired vascular perfusion of the tissues due to edema and angiopathy (including microvascular changes following diabetes mellitus) • Alteration of the normal commensal flora by broad-spectrum antibiotic therapy • Surgical instrumentsand catheters may promote microbial invasion past the anatomical or physiological barriers. • damaged tissues, for example, damaged cardiac valves

13. ANTIBODY DEFICIENCY DISEASES Brutons tyrosine kinase

15. HYPER IgM SYNDROMES Ab switch, memory b cells, somatic hypermutation, dendritic cells to prime t cells,CD80 n 86 upregulation

16. NEMO

17. activation-induced deaminase (AID) uracil-DNA glycosylase (UNG)

19. T AND B CELL IMMUNODEFICIENCIES Next slide

20. SCID; CLASSIFICATION NO STEM CELLS About 15 percent of SCID cases are caused by deficiency of adenosine deaminase(ADA), an enzyme required for the salvage of nucleotides within lymphoid cells. The lack of ADA causes the accumulation of toxic metabolites of adenosine (deoxy- adenosine and deoxy-ATP) within lymphoid cells, resulting in their demise.

21. ARTEMIS

22. Mutations of the tyro-sine phosphatase, CD45, which helps to initiate signaling by the TCR, results in T−B+ SCID in humans. Mutation of components of CD3-complex (CD3 γ, ε, and δ) result in a SCID phenotype. During signal transduction via TCRs, the protein tyrosine kinases Lck and ZAP70 are required for phosphorylation of ITAMs on the intracy- toplasmic segment of the TCR. Deficiency of either of these kinases results in rare forms of SCID.

23. T AND B CELL IMMUNODEFICIENCIES

26. DEFECTS IN INNATE IMMUNITY • TLR signaling: • NEMO (IKK-γ) is the regulatory subunit of the inhibitor of IκB kinase (IKK) complex…activation of genes involved in inflammation, immunity, cell survival, and other pathways….Results in IL, TNF...deficiency leads to more susceptibility to mycobacteria, gram+ and - ,fungi, virus • TLR3 …herpes simplex encephalitis, • Downstream of TLR • CXCR4.. (sdf1, homing)…gain of function mutation...WHIM syndrome…Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo)..Neutropenia. • STAT3…(IL6 n 10) essential for TH17 function beta defensins...bactericidal • HIES… hyper IgE syndrome • IRAK4, STAT1

29. Defects in Leucocyte Migration LAD1 n LAD2 • protein lymphocyte function-associated antigen-1(LFA-1) LFA- 1 expressed on the leucocyte surface and its ligand intercellular adhesion molecule- 1 (ICAM-1) expressed on the luminal surface of activated endothelial cells. • a common β chain (CD18) with three separate α chains called CD11a, b, and c. • CD18-CD11a heterodimers form LFA-1,

30. LAD1 • CD18/CD11b Heterodimers form complement receptor 3, (CR3) • CD18 combined to CD11c forms complement receptor 4 (CR4). • Mutation of the gene encoding CD18 (resulting in the lack of expression of LFA-1, CR3, and CR4) results in an inherited primary immunodeficiency called leukocyte adhesion deficiency type 1(LAD1). LAD2 sialylLewisX, which is expressed on the surface of leucocytes,

31. Mutations of the enzyme GDP-fucosyltransferase prevents post- transcriptional fucosylation of proteins. Such individuals cannot synthesize sialylLewisX. This condition is called leucocyte adhesion deficiency type 2 (LAD2). CLINICAL MANIFESTATIONS: These patients typically present in early childhood with recurrent pyogenic infection of skin, respiratory, and gastro- intestinal tracts as well as mucous mem- branes. Poor wound healing and delayed umbilical cord separation are typical. Because of impaired neutrophil migration, these patients develop a leucocytosis and pus fails to form at sites of infection. These inherited disorders are typically associated with severe gingivitis and periodontal disease, again indicating the particular importance of normal neutrophil function for maintenance of the health of the den- tal crevice. Outcome in both conditions is poor, with early death. BMT is curative in LAD1, and oral fucose supplementation is beneficial in LAD2.

32. On initial characterisation, Th17 cells were broadly implicated in autoimmune disease, and auto-specific Th17 cells were shown to be highly pathologic. A more natural role for Th17 cells is suggested by studies that have demonstrated preferential induction of IL-17 in cases of host infection with various bacterial and fungal species. Th17 cells primarily produce two main members of the IL-17 family, IL-17A and IL-17F, which are involved in the recruitment, activation and migration of neutrophils. These cells also secrete IL-21 and IL-22. Recently, Th17 polarized cells have been shown to mediate the regression of established tumors in mice.[9][10] Whether the highly inflammatory nature of Th17 cells is sufficient to cause or contribute to carcinogenesis is the subject of current debate.[11]