primary immunodeficiencies

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what is the principal consequence of immunodeficiency?
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increased susceptibility to infection. a secondary immunodeficiency is increased CA risk
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what can immunodeficiencies result from?
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immunodeficiencies can result from defects in: lymphocyte maturation, lymphocyte activation, and defects in effector mechanisms (innate and adaptive)
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can pts with certain immunodeficiencies be at risk for autoimmunity?
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yes, pts with certain immunodeficiencies have an increased risk for autoimmunity
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of the (rare) primary immunodeficiencies, what is the most common?
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antibody deficiency @ 50%, followed by severe combined (antibody and cell mediated) @ 20%, followed closely by phagocytic disorders @ 18%
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terminal MAC complement deficiency =
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neisseria meningitidis
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what are the functional deficiencies and mechanism of defect with chronic granulomatus disease?
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recurrent bacterial and fungal infections due to defective ROS production
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what are the functional deficiencies and mechanism of defect with leukocyte adhesion deficiency 1&2?
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both leukocyte adhesion deficiency 1&2 lead to recurrent bacterial & fungal infection, with LAD 1: due to decreased/absent expression of beta 2 integrins w/LAD2: due to decreased/absent expression for ligands E- / P- selectins, leading to faiure of leukocyte migration
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what are the functional deficiencies and mechanism of defect with chediak-higashi syndrome?
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pts w/chediak-higashi syndrome will suffer recurrent infection by pyogenic bacteria, caused by defective vesicle fusion and lysosomal function
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what are the functional deficiencies and mechanism of defect with TLR signalling defects?
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recurrent infection caused by defective vesicle fusion and lysosoma function
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how do B and T cells deficiencies affect serum Ig levels?
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B cell deficiency: serum Ig levels reduced T cell deficiency: serum Ig levels reduced or normal (but no class switching)
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how do B and T cells deficiencies affect DTH rxns to common recall antigens?
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B cell deficiency: normal T cell deficiency: reduced or absent
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how do B and T cells deficiencies affect morphology of lymphoid tissue?
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B cell deficiency: absent or reduced follicles & germinal centers T cell deficiency: usually normal follicles, there may be reduced parafollicular cortical regions
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how do B and T cells deficiencies affect susceptibility to infection?
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B cell deficiency: susceptibility to pyogenic bacteria, enteric bacteria, viruses, and some parasites (extracellular infections esp giardia) T cell deficiency: many viruses, atypical mycobacteria, intracellular bacteria, and fungi (intracellular infections/candia)
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where is the problem with SCID?
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at the differentiation step of the common lymphoid progenitor
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where is the problem with X-linked agammaglobinemia?
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pre-B cell maturation
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where is the problem with hyper-IgM syndrome?
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B cell class-switching (specifically with the CD40L)
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where is the problem with digeorge?
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T cell differentiation
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what does a problem with class II MHC deficiency affect?
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CD4 cells and their interactions (class I problems just affect CD8)
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what are the primary B cell deficiencies?
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X-linked agammaglobulinemia, IgA deficiency, IgG subclass deficiency, hyperIgM syndrome, and common variable immunodeficiency (CVID)
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what is bruton’s x-linked agammaglobulinemia? why does it happen?
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an inablity of pro- pre- B cells to develop into mature B cells. it is caused by maturation being blocked after rearrangement of the heavy chain gene due to the absence of the require tyrosine kinase (btk) which is important for transducing signals from the BCR that trigger differentiation
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what is the consequence of bruton’s x-linked agammaglobulinemia?
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a severe depression/virtual absence of all classes of Ig and a near absence of mature B cells in the blood, bone marrow, spleen, and lymph nodes. the lymph nodes are small and NO tonsils. (*sick pt w/no signs of lymphadenopathy)
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when do you see bruton’s x-linked agammaglobulinemia manifest itself? who gets it?
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in males around 5-6 months of age, b/c this is when maternal antibodies start to fade out. (rare- 1:100,000)
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what are clinical manifestations of bruton’s x-linked agammaglobulinemia? what are common causative BACTERIAL organisms?
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otitis media, bronchitis, septicemia, pneumonia, arthritis, meningitis, dermatitis usually caused bacteria-wise by hemophilus influenzae, streptococcus pneumoniae, staphylococcus aureus, streptococcus pyogenes (extracellular bacteria w/polysaccharide capsules -> pyogenic bacteria)
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what are common causative VIRAL organisms of infections in pts w/bruton’s x-linked agammaglobulinemia?
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enteroviruses (echoviruses, polioviruses, and coxsackieviruses) – these viruses infect the GI and disseminate to the nervous tissue via blood
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what is a common causative PROTOZOAL organism of infection in pts w/bruton’s x-linked agammaglobulinemia? why?
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giardia lamblia b/c resistance is mediated by IgA , however most viral/protozoal, and fungal diseases are handled normally due to intact T cell mediated immunity
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what the accepted treatment for bruton’s x-linked agammaglobulinemia? what is the prognosis for pt’s afflicted w/it?
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injections of large amounts of IgG, and prognosis is death at 20-30 years due to chronic lung disease caused by repeated infection
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what is another cause for failure in B cell differentiation?
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defects in lambda 5 (part of the pre-B cell receptor complex)
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what is the most common primary immunodeficiency?
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selective IgA deficiency
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how is selective IgA deficiency aquired?
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selective IgA deficiency can be autosomal dominant or recessive, it can also occur after infection (toxoplasmosis/measles)
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what are clinical manifestations of selective IgA deficiency?
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most pts with selective IgA deficiency are asymptomatic, though some can have repeated GI and respiratory infections (areas w/mucosal surfaces, though less common these days b/c of improved hygiene). it is an immune complex disease (possibly b/c they make more IgG to compensate), there is a higher incidence of allergy (more class switching to IgE), and autoimmune disorders
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what is the major underlying immunologic defect in pts w/selective IgA deficiencies? are there any other Igs or related structures that pts w/selective IgA deficiency have?
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a failure of terminal differentiation to IgA-secreting plasma cells. some pts w/this deficiency also lack IgG2/IgG4. IgA deficiency is also associated in some cases with defects in the receptor for BAFF (cytokine involved in B cell activation)
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what is the treatment for pts w/selective IgA deficiency? what is the prognosis?
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selective IgA deficiency pts are usually given supportive tx and their prognosis is generally excellent
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are there Ig deficiencies in other Igs besides IgA?
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yes, IgM deficiency is rare but can happen and may lead to severe recurrent infections by encapsulated organisms (pneumococci, H. influenzae). there are also very rare instances of deficiencies in some IgG subclasses
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how is hyper-IgM syndrome, where IgG/IgA is deficient but IgM is increased aquired? is there a partially self-reactive anibody made by IgM in this disease? is IgM the only antibody made by individuals with this disorder?
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hyper-IgM is inherited as an X-linked disorder 70% of the time, and affected boys can get severe bacterial infections/pneumocystis (b/c of defective CMI). IgM is the only antibody made in this disorder, many of which are against RBCs, leading to secondary immunodeficiency.
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why are 70% pts w/hyper-IgM syndrome deficient in their ability to make IgA, IgG, and IgE? why is this disease X-linked?
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there is a failure of heavy chain class switching due to a mutation encoding the CD40L (70% of cases), which makes this disease X-linked b/c the CD40L gene is on the X chromosome. because of this mutations, CD4 T cells cannot activate macrophages via CD40:CD40L, leading to impaired resistance to intracellular microbes (no DTH mechanisms)
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what are other causes for the other 30% of hyper-IgM cases? how are they aquired?
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AID (activation-induces deaminase required for class-switchig and affinity maturation), CD40, NEMO (of of the Ikk subunits that regulates NFkB, an important T/B cell signaling component) = all of these are inherited in an autosomal recessive fashion
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what is common variable immunodeficiency?
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common variable immunodeficiency is relatively common, but poorly defined. pts w/this have normal/near normal B cells – but they have hypogammaglobinemia (they make antibodies, but at a much lower level), which can affect all classes of Ig, but sometimes only IgG
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what is the consequence of common variable immunodeficiency?
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impaired antibody response to infection/vaccine due to poor differentiation of B cells into plasma cells
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what are probable defects leading to common variable immunodeficiency? are there some genetic mutations involved? can it be inherited?
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intrinsic B cell defects, abnormalities in T cell activation, however the cause is unknown in a majority of cases. there are some genes found to be mutated: BAFF receptor, and ICOS (an inducible costimulator homologous to CD28/B7). it has a sporatic inheritance pattern.
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when do symptoms of common variable immunodeficiency appear? what are they? how is CIV treated? what is the prognosis?
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common variable immunodeficiency can appear from childhood – mid 30s. it has variable symptoms including increased infection by pyogenic organisms, giardia, sometimes recurrent herpes, high incidence of autoimmune phenomena (RA), high incidence of malignances (lymphoid, gastric). tx for CIV is Ig and the prognosis is excellent.
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what is digeorge syndrome? how is it aquired? what is its prevalence? what is the age of onset?
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digeorge syndrome/thymic hyperplasia is a defective development in the 3rd/4th pharyngeal pouches which can be sporatic, associated with a deletion in chromosome 22, some are associated with maternal alcohol consumption during pregnancy. rarely digeorge syndrome can be caused by an autosomal dominant mutation or translocation involving chromosome 22. it is rare and its onset appears in *newborns.
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what are clinical manifestations of digeorge syndrome?
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facial features: widely separated eyes, low set ears, and the philtrum of the upper lip is shortened. there are congenital malformations of the heart, and the pt will lack the thymus and parathyroids (hypocalcemic, tetany).
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how does digeorge syndrome affect the immune system?
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there is an absence of cell mediated immunity with low numbers of T cells in blood, lymphoid tissue and T cell zones are depleted: paracortical areas of lymph nodes/periarteriolar sheaths of spleen
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what are antibody levels like in digeorge syndrome?
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antibody levels are low to normal and pts fail to mount specific antibody responses (doesn’t make T dependent antibody responses)
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what is treatment for digeorge syndrome? what is the prognosis?
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fetal thymic transplantation or a (non T cell depleted – but risk for GVH disease) bone marrow transplant. the prognosis is generally poor untreated and other defects can complicate (heart problems etc)
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what are common pathogens for pts w/digeorge syndrome?
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repeated infection by viruses, fungi, intracellular bacteria (mycobacteria) and protozoa.
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what makes up the causes for SCID (severe combined immunodeficiency)?
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it is a constellation of genetically distinct disorders, all leading to defects in both humoral (antibody) and cell mediated immunity
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what do infected SCID infants present with?
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oral candidiasis, extensive diaper rash, and failure to thrive
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what is the age of SCID onset? what are clinical manifestations?
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SCID shows up in infancy (after maternal antibody fades out) and presents as susceptibility to any type of microbial infection, (bacterial, viral, fungal, protozoal, ESPECIALLY: cytomegalovirus, pneumocystis, and candida)
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what is the most common underlying immunological defect causing SCID?
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common gamma chain deficiency causes 50-60% of SCID cases and is X-linked. the common gamma chain deficiency of the IL-2R is missing which is used for IL-4,7,11,13,15. the worst of these is problems with IL-7 which is essential for T cell differentiation, (also effects B cells, but not as profoundly)
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why is antibody production low with the common gamma chain deficiency causative in 50-60% of SCID cases? are NK cells affected by this?
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the gamma chain is used in the receptor complex for IL-7, which when IL-7 signalling is not recieved, T cells cannot differentiate and thus can’t help with antibody production. NK cells are also affected b/c IL-15 also used the gamma chain in its receptor.
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how can an autosomal adenosine deaminase deficiency lead to SCID? is there a similar deficiency that can cause a similar issue?
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an ADA deficiency can lead to accumulation of deoxyadenosne and further metabolites that are toxic to rapidly dividing immature lymphocytes, esp those of T cell lineage (B cell numbers affected less). there is also a perinucleotidal phosphorylase deficiency (also autosomal recessive) that causes a similar disease
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what happens if there is a mutation in RAG genes?
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this can block development of T and B lymphocytes – can lead to SCID, but extremely rare in humans. this is because receptor recombination is necesary to drive differentiation
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can mutations in the Jak3 protein kinase cause SCID? what is the inheritance?
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yes, this is an important fast signaling molecule (autosomal recessive)
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can mutations in signaling molecules cause SCID? what is the inheritance?
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yes (autosomal recessive)
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can mutations in class II MHC cause SCID? what is the inheritance?
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yes this is called bare lymphocyte syndrome (autosomal recessive)
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what is the treatment for SCID? is there gene therapy available for the common gamma chain deficiency? what is the prognosis for SCID?
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bone marrow transplant. there is also gene therapy available for the common gamma chain deficiency via a retroviral vector that can reconstitute the immune system for over a year but 20% develop acute T cell leukemia (due to oncogenes in retroviral vector). SCID prognosis if untreated is very poor, though if successfully transplanted: excellent.
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what is wiscott-aldrich syndrome?
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an X-linked disease caused by a mutation in the WASP protein gene. the WASP protein belongs to a family of proteins that link membrane receptors to cytoskeletal elements, and its loss affects signal transduction and cell migration.
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what is wiscott-aldrich syndrome characterized by?
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thrombocytopenia (petechiae), eczema, and marked vulnerability to recurrent infection
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what happens in pts afflicted by wiscott-aldrich syndrome?
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there is a progressive depletion of T lymphocytes in peripheral blood and T cell areas of lymphoid organs. there is a variable loss of CMI, and antibody production is impaired (Ig against polysaccharides is absent and low against proteins – because even in B cells, cellular signalling via WASP is impaired) IgG is usually normal, but IgM is low -> because this is a progressive loss
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can there be inherited complement deficiencies?
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yes with: C3, MAC components, and the C1 inhibitor
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what happens with C3 deficiency?
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increased susceptibility to serious, recurrent pyogenic infection -> leading to immune complex glomerulonephritis
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what happens with MAC component deficiency?
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loss of C5-9 can lead to increased incidenct of neisseria infection
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what happens with C1 inhibitor deficiency?
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hereditary angioedema

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