Immunodeficiency

primary:Many of these disorders are hereditary/secondary: acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging and particular medications
1. When to suspect? >1 septicaemia, >1 meningitis, >1 pneumonia, >5 chest infections -because usually cleared by immune system. Unusual infections=mycobacterium avium, pneumocystis carinii, invasive candida
Phagocyte immunodeficiencies
1. Neurtropenia- not enough neutrophils, primary: congenital neutropenia. Secondary e.g. chemotherapy
2. Chronic granulomatous disease- phagocytes unable to kill certain organisms (bacteria-staphylococcus aureus/fungi-aspergillus fumigatus).
  1. Phagocyte killing by respiratory burst=Reaction equation
  2. Defective phagocyte killing- failure of phagocytes to kill ingested microbes due to defective production of free radicals & other toxic molecules.
  3. Rare disease, usually diagnosed in infancy. Patients experience recurrent infections (bacterial and fungal) not normally observed in healthy patients. Antimicrobial drugs and IFNy used for CGD treatment
  4. Defects caused by mutations in subunits of the superoxide generating NADPH-oxidase enzyme. X-linked form most common-effects gp91 subunit of NAPHH oxidase. Other forms are autosomal recessive-affects other subunits
3. Leucocyte adhesion deficiency
  1. Rare disease. Phagocytes unable to migrate to tissues, blood cells build up in blood, patients susceptible to most bacterial and fungi. Defect with molecule LFA-1 (CD18)
Complement deficiencies
1. Defects in early C proteins (C1, C2,C4)=autoimmune diseases-SLE very common & sometimes RA
2. Defects in MAC formation (C5-C9)- neisseria assocated meningococcal disease & gonorrhoea
3. Properdin deficiency (activates alt pathway)-neisseria associated meningococcal disease
4. MBL deficiency (lectin pathway)-resp infections in children & autoimmune problems
  1. MBL is polymorphic-this genetic variation confers differing MBL levels. Range from 5ng/ml to 10 in serum. Atleast 5% of popn have low MBL haplotype-not strongly associated with increased disease susceptibility like many other immunodeficicncies- illustrates redundancy in immune sys-because have classical pathway still so not serious effects. Risk of infection greater in young children especially during the 'window of vulnerability' prior to maturation of adaptive immunity. Association with autoimmune diseases suggests a complex reg role of MBL. Treatment: MBL replacement therapy.
5. Regulatory defects- cascade overactivated where it shouldnt be: Clq inhibitor defect- hereditary angioedema/ DAf deficiency-paroxysmal nocturnal hemoglobinuria (spont. RBC lysis)/ Factor H deficiency-various renal complications
Macrophage activation defects
1. Macrophage infected with bacteria signal to T cells (IL-12) which then signal the macrophage to kill the bacteria (IFNy)
  1. IFNy binds IFNy receptor-activates Jack/STAT pathway of signalling molecule-switches on txn of interferon responsive genes
2. Type I cytokine deficiency- salmonella, mycobacterial disease (which live inside the macrophage)
3. IFNy defects
  1. mutation of IFN y receptor-autosomal recessive (must have defect on both copies), common in inbred families. Patients do not display increased susceptiblity to other intracellular pathogens suggests IFNy signalling has crucial role in immunity against mycobacteria. Observed mostly in young children
4. IL-12 defects
  1. Mutation of IL-12 receptor causes inability to respond to IL12=defective IL12 production. Presents at variable ages
5. STAT1 defects- mutated STAT1 txn factor-defective IFNy respnses (usually triggers production of interferon response genes)
Antibody deficiency
1. Bacterial infections and viral infections to a smaller extent (except enterovirus)
2. Spleen
  1. Blood filter-removes damaged red cells, stores platelets, immune responses-major secondary lymphoid organ
  2. Asplenia (Congenital)-septicaemia (blood poisoning)=reduced responses to polysaccharide Ags, thrombocytosis (high platelet count)
  3. Asplenia (acquired)=due to splenectomy to correct abnormal splenic function=englarged spleen in malaria, some leukaemia's and lymphomas, car crash. Removal of spleen requires follow up vaccination
3. SCID-severe combined immunodeficiency
  1. Defects affect wither T cells or T cells & B cells. Patients have very low lymphocyte numbers, normal RBC & myeloid cells= Lack of T cell responses, B cell defects can be masked by presence of maternal Abs, severe infections (viral & fungal)-usually lethal, confinement of patient to sterile environment usually required, treated by stem cell transplantatio (restore cells with infective genes)
  2. Can be due to mutations in no. of important genes: IL=2Ry chain gene, JAK3 deficiency, RAG-1/-2 genes/ ZAP-70
4. CVID-common variable immunodeficiency
  1. B cell disorder. Low Ab levels (IgM,IgG,IgA)-hypogammaglobulinemia. Recurrent infections usually later in life. Genetic defects not fully defined. Defective maturation of B cells into plasma cells or defect in Ab production. Treatment by immunoglobin therapy
5. XLA-X linked agammaglobulinemia
  1. More common in males, male patient will pass on the gene to any daughters-with one abnormal copy=carriers but their sons at risk. Deficiency in B cells. Mutation in BTk gene-affects B cell development. Recurrent infections. Even live attenuated vaccines cannot be handled by XLA patients. Treated by immunoglobulin therapy
AIDS
1. Epidemic. HIV-1 )RNA virus). Patients display symptoms of opportunistic infections-TB, malaria, pneumonia or cancer. Decrease in CD4+ T cells. HIV-1 attached to and infect CD4+ T cells=form syncytia (giant cells)-infected T cells are rapidly killed. Defective delayed type hypersensivity to Ag. Elevated IgG & IgA production, reduced IgM

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Immunodeficiency

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