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Primary immunodeficiency disorders affect what 4 components of the immune system?
- Innate: phagocytic cells, complement
- Adaptive: B cells, T cells
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Types of phagocytic cell disorders
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Quantitative defects of phagocytic cells
- Neutropenia (congenital or acquired)--> increased susceptibility to bacterial infection
- Hyposlpenism (reduced number of macrophages in surgical splenectomy - if spleen removed, more susceptible to infection)
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Defect of granule formation and content (qualitative phagocytic cell disoder)
Chediak-Higashi
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Defect in the fusion of phagosome and lysosome
Chediak-Higashi
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Characteristics of Chediak-Higashi
- Partial albinism
- Giant lysosomes
- Low NL and CTL
- Impaired lysosomal trafficking
- Recurrent BACTERIAL infection
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Qualitative cell disorder characterized by defects in oxidative metabolism
Chronic granulomatous disease
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Chronic granulomatous disease
Immune system has difficulty forming the reactive oxygen compound used to kill certain ingested pathogens --> formation of granulomas in many organs
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Pathway that is deficient in chronic granulomatous disease
Hexose monophosphate
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Enzyme complex required by phagocytes to produce reactive oxygen species
PHOX (phagocyte NADPH oxidase)
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Symptoms of chronic granulomatous disease
- Skin lesions --> large granulomatous masses
- Recurrent fever, pyoderma, pneumonia
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Test used to evaluate PHOX activity
NBT test
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Product produced by normal PHOX activity
- HOCl (bleach)
- Bleach is most important killing mechanism in cells
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Most common PHOX deficiency
GP91PHOX
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Disease with defective adherence and chemotaxis due to integrin defect
Leukocyte adhesion disease 1(LAD1)
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Disease with defective adherence due to selectin fucosylation defect on the rolling cell
Leukocyte adhesion disease 2 (LAD2)
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Symptoms of LAD1
- Delayed cord separation
- Skin ulcers
- Periodontitis
- Leukocytosis
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Symptoms of LAD2
- Recurrent infections (cell can't get into tissue)
- Mental retardation
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In what cells does latent TB effect?
Macrophages
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What is formed when bacteria is taken up into a macrophage?
IL-12
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Action of IL-12 on T cell
Stimulates T cell to produce IL-2 and then make interferon γ
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Action of interferon-γ on macrophage
Binds interferon-γ receptor --> macrophage activated via nF-KB pathway --> killing of bacteria
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Consequence in deficiency in IL-12/interferon-γ pathway
Can't kill INTRACELLULAR bacteria (e.g. salmonella, TB) -> recurrent salmonella, TB infections
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Are staph and strep intracellular or extracellular pathogens?
Extracellular
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Are salmonella and TB intracellular or extracellular pathogens
Intracellular
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TLR responsible for recognizing LPS
TLR-4
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TLR responsible for recognizing DNA, RNA motifs
TLR-8,9
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EDA-ID
Ectodermal dysplasia with immunodeficiency
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NEMO
- Non-essential modulator of the nF-KB signalling pathway
- Important for cytokine signalling pathways
- Activates other enzyme complexes to translocate into nucleus and initiate transciption
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Symptoms of ectodermal dysplasia
- Abnormal development of teeth, hair, nails, sweat glands (-->anhidrosis)
- Frequent recurrent infections of gram neg rods, gram + cocci, pneumocystic pneumonia, CMV, mycobacteria
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Mutation that causes IRAK4
IL-1 receptor associated kinase (component of TLR signalling pathway)
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Symptoms of IRAK4
- Pneumococcal meningitis
- Meningococcal meningitis
- Staph infection
- Pseudomonas
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What do deficiencies in UNC93B1 and TLR3 deficiences cause increased susceptibility for?
HSV-1 --> encephalitis, meningitis
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Early complement deficiencies are associated with what 2 autoimmune diseases?
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Disease caused by C1 inhibitor deficiency
Hereditary angioedema
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Consequences of C3 deficiency
Recurrent gram + infections
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Consequences of late complement deficiences
Recurrent gram - infections (ex. neisseria)
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BTK
Bruton's tyrosine kinase
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What condition is associated with a deficiency in BTK?
Agammaglobulinemia
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Symptoms of agammaglobulinemia
- Repeated infection with same pathogens (no memory response)
- Infections by pyogenic encapsulated bacteria (high grade infections)
- Lots of infections
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CVI
Common variable immunodeficiency
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Problem associated with CVI
Panyhypogammaglobulinemia (patient doesn't produce specific antibodies vs. pathogens)
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Combined defect of T and B system
SCID
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Specific deficiency associated with SCID
γ chain in the receptors for IL-2,4,7,9,15,21
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Mutatations in what genes are associated with Omenn's syndrome
- RAGs (recombination activating genes)
- Effects circulating levels of B and T cells
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Job's syndrome
- Elevated IgE
- Poor antibody and cell-mediated responsess
- Staph infections
- Pneumonia, pneumatocoeles
- Eczema
- Eosinophilia
- Course facial features
- Don't lose baby teeth
- Boils
- Nail infections
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Deficiency associated with hyper IgE
STAT3 (signal transducer and activator of transcription)
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IPEX
Immune disregulation, polyendocrinopathy, enteropathy, X-linked
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Deficiency associated with IPEX
- Lack of T-reg cells (i.e. CD4+, CD25+, FoxP3+ cells)
- --> problems with liver, endocrine organs, autoimmune diarrhea, ezcema
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DNA repair defect associated with brain and immune system
Ataxia telangiectasia
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Chronic mucocutaneous candiadias
- Severe T cell problem
- Chronic fungal infections
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Symptoms associated with DiGeorge's syndrome
- Athymia
- Facial defects
- Heart defects
- Recurrent infections of viruses, fungi, mycobacteria
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