Immunodeficiency Diseases PDF

Primary Immunodeficiencies Rare congenital diseases which manifest early in life, characterised by a history of repeated infections, often with the same or similar pathogens (often opportunistic) ○ Caused by mutations to recessive genes (commonly X-linked) The clinical effec...

Primary Immunodeficiencies Rare congenital diseases which manifest early in life, characterised by a history of repeated infections, often with the same or similar pathogens (often opportunistic) ○ Caused by mutations to recessive genes (commonly X-linked) The clinical effect varies because mutations affect different genes which encode different molecules, thus having differing follow on effects to specific parts of the immune system, thus will have different vulnerabilities Even mutations to the same gene can have varying effect (point; only slight effect, frameshift; can shorten or abolish proteins, mutations in promoter regions may alter expression Eg. In IgA deficiency 25% of people have poor mucosal immunity and 75% cases are nearly asymptomatic Secondary Immunodeficiencies Acquired later in life from environmental factors such as: ○ Infection (HIV, measles, malaria) ○ Malnutrition (causing T cell deficiency) ○ Cancer ○ Medical treatments (chemotherapy, radiotherapy and immunosuppressive drugs) General Features of Immunodeficiency Diseases B cell deficiencies: ○ Consequences: pyogenic bacterial infections T cell deficiencies: ○ Consequences: viral and other intracellular microbial infections and virus-associated malignancies Innate immune deficiencies: ○ Consequences: variable but an increase in pyogenic bacterial infections Chronic Granulomatous Disease Characterised by an undue susceptibility to persistent bacterial and fungal infection in the first 2 years of life by organisms that are non-pathogenic ○ These heal slowly, forming granulomas These occur when an intracellular pathogen cannot be eliminated and infects macrophages, fused macrophages and Th1 cells ○ Causes pneumonia, lymphadenitis, skin abscesses and visceral infection and is treated with prophylactic antibiotics, anti-inflammatories and hematopoietic stem cell transfer Normally, phagocytes (and monocytes) work as anti-bacterial cells through the use of reactive oxygen species made through phagocyte oxidase ○ In CGD, this enzyme (NADPH oxidase, which produces superoxide ions) is mutated on the X chromosome Leukocyte Adhesion Deficiency In this autosomal recessive condition, the phagocytes can function but can’t access the site ○ Normally, macrophages have selectins which slow the cell down and integrins which bind strongly to allow the macrophage to extravasate In LAD, there is defect in the CD18/beta2 integrin (phagocytosis is also impacted as Mac1 is a complement receptor) A rarer type has a selectin defect instead Causes severe recurrent bacterial infections that are eventually fatal if untreated (generally from genuine rather than opportunistic pathogens) and it treated with prophylactic antibiotics and bone marrow transplants ○ Commonly also presents with: severe gingivitis, high white blood cells, normal antibody responses and delays in wound healing Severe Combined Immunodeficiency SCID is a series of genetic defects that affect the development of T cells and sometimes B cells and NK cells as well and presents with few lymphocytes in the periphery with an almost completely lacking T cell based immunity and T cell antibody response ○ It affects thymic development, disrupting the medulla and cortex, affecting the maturation of cells There are three main genetic causes: ○ X-linked SCID: common cytokine gamma chain receptor deficiency: No T cells or NK cells, B cells have normal numbers Common gamma chains (2, 4 and 7) have a signalling role don’t signal and thus don’t cause phosphorylation, especially towards IL-7 (which promotes development) Severe Combined Immunodeficiency cont. There are three main genetic causes: ○ RAG (recombination activating genes)-1/2 enzymes (autosomal): No T cells or B cells RAG is an enzyme which recombines the functional components of the antibodies Without it, lymphocytes can’t express receptors to get positively selected ○ Purine Salvage Pathway Enzymes (autosomal): No T cells, B cells or NK cells These normally catabolise nucleic acids, where a deficiency leads to an accumulation of toxic metabolites SCID Outcomes and Treatment Outcomes: ○ Patients will survive the first few months as they are protected by maternal antibodies before developing severe opportunistic infections (normally thrush in the mouth or nappy area first) ○ Commonly have coughs or pneumonia from viral infections ○ Intractable (difficult to manage) diarrhoea from viruses or E. coli Treatment: ○ Prophylactic antibiotics ○ Intravenous immunoglobulins ○ Hygiene measures ○ Avoidance of live attenuated vaccines ○ Patients die in a month without this Antibody Deficiencies This is termed X-linked agammaglobulinemia with hyper-IgM ○ It has very high IgM and low or absent IgG, IgA and IgE It is a defect in isotype switching (makes IgM but nothing else) This switching is isotype dependent, occuring in germinal centres, driven by cytokines and CD40L:CD40 (CD40 is the X-linked mutation) Because they have IgM however, they are limited immunity not none, IgM is good at activating complement but not good at neutralising toxins or opsonisation ○ Plasma cells exist but germinal centres (which occur during humoural immune responses and indicative of a good B cell response) are lacking ○ Normally normal blood lymphocytes but there can be neutropenia ○ There are recurrent pyogenic bacterial infections and some susceptibility to opportunistic pathogens Treatment: IV gamma-globulin, prophylactic antibody, HSCT Defects in T-Cell Activation Condition is X-linked lymphoproliferative syndrome ○ 3 phenotypes: Fulminating infectious mononucleosis (inability to control Epstein Barr virus infection) Causing B cell lymphomas and/or lymphoproliferation Dysgammaglobulinaemia which can progress into hypogammaglobulinemia These are related to SAP and SLAM molecules ○ SAP plays a role in signal transduction by binding to phosphotyrosine residues There are also a family of SLAM proteins on leukocytes which express via tyrosine residues SLAM and SAP are expressed on NK and CTL cells Normally these will signal, enhancing the killing of an infected cell (infected B cell or a transformed B cell lymphoma) but without SAP, SLAM can’t signal