Transcript clinical genetics immune disorders

9. IMMUNOGENETICS
10.GENETIC DISORDERS OF THE IMMUNE SYSTEM
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.
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.
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. Germline p53 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.
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.
CAUSES
1. DNA DAMAGE
IMMUNODEFICIENCY
impaired function of the immune system (immunodeficiency) resulting in increased
susceptibility to infection.
Primary immunodeficiency-PID
intrinsic defect of a component of the immune Most by defects in single genes and are hence
heritable.. rare
Secondary or acquired
secondary to another pathological condition, which adversely affects immune function,
From a clinical perspective, immuno- deficiencies can be classified into eight categories
DEFECTS IN ANATOMICAL OR PHYSIOLOGICAL BARRIERS TO INFECTION
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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 instruments and catheters may promote microbial invasion past the
anatomical or physiological barriers.
damaged tissues, for example, damaged cardiac valves
ANTIBODY DEFICIENCY DISEASES
Brutons tyrosine kinase
HYPER IgM SYNDROMES
Ab switch, memory b cells, somatic hypermutation, dendritic cells to prime t
cells,CD80 n 86 upregulation
NEMO
activation-induced deaminase (AID)
uracil-DNA glycosylase (UNG)
T AND B CELL IMMUNODEFICIENCIES
Next slide
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.
ARTEMIS
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 intracytoplasmic segment of the TCR. Deficiency of
either of these kinases results in rare forms of
SCID.
T AND B CELL IMMUNODEFICIENCIES
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 i
the bone marrow (myelo).. Neutropenia.
• STAT3…(IL6 n 10) essential for TH17 function beta defensins...bactericid
• HIES… hyper IgE syndrome
• IRAK4, STAT1
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,
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
sialyl LewisX, which is expressed on the surface of leucocytes,
Mutations of the enzyme GDP-fucosyl transferase prevents post- transcriptional
fucosylation of proteins. Such individuals cannot synthesize sialyl LewisX. 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.
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]