L28: Immunodeficiency Flashcards
Immunodeficiencies (3 subdivisions)
- Primary immunodeficiency: genetic defect resulting in weaker or absent immune response
- Secondary immunodeficiency: weakened or absent immune response as a result of another disease or condition
- Immunosuppression, weakened immune response: either pharmacologic, normal or part of another condition
Genetics of immunodeficiencies
Most genetic defects are recessive, thus most are X-linked and most occurring in males. Females are carriers but are usually healthy. Mapping of X-linked immune deficiencies show that there is no particular region in which mutation matters.
X-linked Agammaglobulinaemia (XLA)
Failure of a child to produce antibodies noticed once the child is older than 6 months. Babies are born with high levels of IgG. After birth, IgM production starts rapidly however IgG production does not start till after 6 months at which maternal IgG is reduced. Defective gene in XLA encodes a tyrosine kinase: btk which couples BCR to nuclear events resulting in proliferation and differentiation of pre-B cells. Pre-B cells missing btk do not proliferate and differentiate into Ig-secreting plasma cells. Pre-B cell receptors transduce signal via btk for B cell development. In males, this defect leads to XLA while in females there is inactivation of the defective chromosome or inactivation of the normal X chromosome. Mature B cells of carrier females will always have the defective X chromosome.
Bruton’s tyrosine kinase (Btk)
Belongs to TEC family of kinases involved in B/T receptor signalling. Btk links the cell receptor to the generation of the second messengers IP3 and Calcium. When the BCR is ligated, the tyrosine kinase syk phosphorylates it. Btk associates with this complex and phosphorulates and activates PLCy which cleaves PIP3 to generate IP3 opening calcium channels. These 2nd messengers results in B cell proliferation and differentiation. If btk is mutated, there is no proliferation or differentiation of B cells.
Severe combined immunodeficiency disease (SCID)
Covers a range of disorders where both antibody and cell-mediated immunity is impaired. Stem cells fail to differentiate into T/B cells and are prone to any microbial infection. Bone marrow transplant is the best treatment.
X-linked SCID
T cells fail to develop due to mutation in the common gamma chain of cytokine receptors (IL2, 4, 7, 9 and 15). The gamma chain is necessary for intracellular signalling. Defects in IL7 receptor causes failure of T cells to develop as it stimulates growth of pre-T cells in bone marrow
Phagocytic dysfunctions
Defects during phagocytosis leading to reduced phagocytic killing. Symptoms include infections with low virulence organisms and reduced pus formation
Chronic granulomatous disease (CGD)
Due to mutations within the NDAPH oxidase system of phagocytes. There is decreased killing as the phagocytes cannot produce toxic oxygen metabolites. Symptoms usually appear in the first 2 years of line. Patients have increased susceptibility to bacterial infections and certain fungi
Complement deficiencies
Absent dysfunctional molecule in the complement cascade. Deficiencies in C1, 2 and 4 lead to increases susceptibility to autoimmune disease. Deficiencies in C5-C8 lead to recurrent infections
AIDS
Linked with Human Immunodeficiency Virus (HIV). Two strains: HIV1/2. Primary infection with HIV can cause transient flu-like symptoms. An adaptive immune response follows controlling the acute illness and restoring CD4 cell numbers. Long period of quiescence (clinical latency) where there is gradual decline in CD4 T cell numbers, dropping below 500uL will allow opportunistic infections and symptoms to appear and 200uL = full-blown aids.
HIV
Retrovirus (RNA genome), envelope proteins include two noncovalently linked glycoproteins (gp120/41). Gp120 associates with high affinity to cell surface CD4 and is reason why HIV primarily infects CD4+ T cells, and macrophages/DCs which express low levels of CD4. HIV also bind with low affinity to chemokine receptors: CCR5, required to infect a cell.
Gp120/gp41
Gp120 on virus binds to CD4 on T cell, changes conformation and binds to CCR5. Gp41 gets released and causes fusion of viral envelope with the T cell plasma membrane. Once inside the cell, reverse transcriptase is activated and a dsDNA genome is generated which integrates into the host cell DNA to become a provirus.
HIV cell tropism
Dependent of co-receptor, if virus has preference for CCR5 it will attack macrophages, CXCR4 will attack lymphocutes. Natural mutation in CCR5 causing no cell expression = resistance to HIV infection
Cyclosporine - immunosuppressive drug
Inhibits activation of T cell transcription factor NFAT by the inhibition of calcineurin. CsA binds to the cytosolic protein cyclophilin (CpN) in T cells. The CsA-CpN complex blocks the function of the enzyme calcineurin (CaN) which has a phosphatase activity. As a result CaN fails to dephosphorylate the transcription factor, nuclear factor of activated T cells (NF-ATc), and thereby inhibits NF-ATc transport to the nucleus. NF-ATc is unable to bind to the NF-ATn, inhibition production of IL2, therefore IL-2 dependent T cell proliferation is inhibited.
