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148 Cards in this Set
- Front
- Back
when do most primary immunodeficiencies manifest themselves
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btwn 6 months and 2 years of life
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characteristics of X-linked agammaglobulinemia (Bruton's agammaglobulinemia)
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failure of B cells precursors to dvlp into mature B cells; B cells absent/decreased markedly; serum IgGs depressed; germinal centers underdeveloped; plasma cells absent; T-cell mediated rxns normal
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mutation in X-linked agammaglobulinemia
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in cytoplasmic tyrosine kinase called Bruton tyrosine kinase (Btk)
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Btk fxn
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associated with Ig receptor complex of pre-B and mature B cells and is needed to transduce signals from the receptor
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what happens due to mutation in Btk
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light chains not produced-complete antigen receptor molecule cannot be assembled and transported to cell membrane
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when does X-linked agammaglobulinemia become evident
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~6 months once maternal immunoglobulins depleted-recurrent infections
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causative recurrent infection organisms in X-linked agammaglobulinemia
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H influenzae, Strep pneumoniae, Staph aureus
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why are X-linked agammaglobulinemia ppl susceptible to enteroviruses like echovirus, poliovirus, and coxsackievirus
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antibodies are important for neutralizing viruses in bloodstream or mucosal secretions or being passed from cell to cell
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autoimmunity and X-linked agammaglobulinemia
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up to 35%; breakdown of self tolerance likely
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treatment of X-linked agammaglobulinemia
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replacement therapy with immunoglobulins
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common variable immunodeficiency
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hypogammaglobulinemia; diagnosis based on exclusion of other well-defined causes of decreased antibody production
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X-linked agammaglobulinemia vs common variable immunodeficiency
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most with common variable have normal amounts of B cells in blood and lymph tissues, but they aren't able to differentiate into plasma cells
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cytokine BAFF
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promotes survival and differentiation of B cells; minority of common variable immunodeficiency have mutation in
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ICOS (inducible costimulator)
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homologous to CD28 and is involved in T cell activation and interactions btwn T and B cells; minority of common variable immunodeficiency have mutation in
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onset of symtoms in common variable immunodeficiency
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childhood or adolescence
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common variable immunodeficiency and other disease associations
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autoimmune 20%; increased lymphoid malignancy; increase gastric cancer
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isolated IgA deficiency
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familial or aquired (viruses); low IgA in both serum and sercretory
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where do infections occur with IgA deficiency
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respiratory, GI, and GU
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Hyper-IgM syndrome characteristics
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make IgM antibodies, but are deficient in IgG, IgA, and IgE; helper T cells defective in delivering activating signals to B cells and macrophages; # B and T cells normal
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X-linked hyper IgM
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70% cases; mutation in gene encoding CD40L
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autosomal recessive hyper-IgM syndrome
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CD40 mutation or enzyme called activation-induced deaminase
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activation-induced deaminase fxn
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DNA-editing cytosine that is required for class switching and affinity maturation
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what can the IgM in hyper-IgM syndrome cause
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may react with elements of blood and give rise to hemolytic anemia, thrombocytopenia, and neutropenia
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how do patients with hyper-IgM syndrome present
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recurrent pyogenic infections
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DiGeorge syndrome (thymic hypoplasia) characteristics
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T-cell deficiency due to failure of dvlp 3rd and 4th pharyngeal pouches; also, tetany, and congenital defects of heart and great vessels; appearance of mouth, ears, and facies may be abnormal
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what does the 4th pharyngeal pouch give rise to
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thymus, parathyroid glands, some of the clear cells of the thymus, and the ultimobranchial body
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Ig levels in Digeorge
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may be normal or reduced, depedning on severity of T-cell deficiency
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what causes Digeorge syndrome
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deletion of 22q11 in 90% patients; T-box family of transcription factors-dvlp of branchial arch and great vessels
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Severe Combined Immunodeficiency (SCID) characteristics
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defects in humoral and cell-mediated immunity; recurrent, severe infections; bone marrow transplant necessary in 1st year of life
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how do infants with SCID present
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thrush prominent, extensive diaper rash, failure to thrive
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most common form of SCID cause
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50-60%; X-linked; mutation in common gamma-chain subunit of cytokine receptors
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function of gamma-chain subunit of cytokine receptors
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part of signal transducing components of receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL15, and IL-21
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what is IL-7 required for
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survival and proliferation of lymphoid progenitors, paticularly T-cell precursors
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IL-15 fxn
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maturation and proliferation of NK cells
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most common autosomal recessive SCID cause
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deficiency of enzyme adenosine deaminase (ADA)
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why does ADA deficiency cause SCID
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mechanism not clear-possibly accumulation of seoxyadenosine and derivatives which are toxic to rapidly dividing immature lymphocytes
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Jak3
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intracellular kinase essential for signal transduction through common cytokine receptor gamma chain
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bare lymphocyte syndrome
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mutations in transcription factors required for class II MHC gene expression
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thymus in SCID due to ADA deficiency
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remnant of Hassall's corpuscles can be found; lymphoid tissues hypoplastic
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treatment of SCID
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gene therapy available-20% dvlp acute T-cell lymphomas; bone marrow transplant
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Immunodeficiency with Thrombocytopenia and eczema (Wiskott-Aldrich syndrome)
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X-linked recessive; thymus morphologically normal; progressive depletion of T cells in peripheral blood and T-cell zones; don't make antibodies to polysaccharide antigens
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Immunoglobulins in Wiskott-Aldrich syndrome
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IgM low, IgG usually normal; IgA and IgE often elevated
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what causes Wiskott-Aldrich syndrome
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mutations in Wiskott-Aldrich syndrome protein (WASP)
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WASP fxn
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link membrane receptors to cytoskeletal elements; may be involved in cell migration and signal transduction
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treatment of Wiskott-Aldrich syndrome
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bone marrow transplant
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C3 component of complement
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required for classical and alternative pathways
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immune-complex mediated inflammation in absence of complement
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by Fc receptor-dependent leukocyte activation; can cause increase incidence of glomerulonephritis
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C6, 7, 8, 9
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required for assembly of membrane attack complex involved in lysis of organisms
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absense of C6 to 9 increases incidence of
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neisserial (gonococcal and meningococcal) infections
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C1 inhibitor deficiency causes
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hereditary angiodema; targets C1r and C1s enzymes, factor XII of coagulation pathway, and kallikrein system
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hereditary angiodema characteristics
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episodes of edema affecting skin and mucosal surfaces such as larynx and GI tract
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paroxysmal noctural hemoglobinuria
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mutations in enzymes required for glycophosphatidyl inositol linkages (assemble decay-accelerating factor and CD59); uncontrolled complement activation on surface of RBCs
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hemolytic uremic syndrome
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microvascular thrombosis in kidneys; mutations in protein factor H cause 10% cases
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viral transmission of HIV
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1) direct innoculation into blood vessels breached by trauma 2) infection of dendritic cells or CD4+ cells within mucosa
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risk of HIV in transfused blood
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1 in 2 million units
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what increases baby risk of HIV infection from mother
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mother low CD4+ count, high viral load, chorioamnionitis
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HIV from needle stick
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0.3%, reduced 8 fold if given antiretroviral therapy within 24 to 48 hours
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HIV specs
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nontransforming human retrovirus from lentivirus family; 2 forms HIV-1 and HIV-2, 1 more common in US; spherical
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major capsid protein in HIV
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p24; most readily detected ciral antigen
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3 viral enzymes in core of HIV
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protease, reverse transcriptase, and integrase
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what are HIV glycoproteins gp120 and gp41 critical for
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infection of cells; they stud the viral envelope
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tat gene of HIV
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causes 1000-fold increase in virus replication; critical for replication
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where is most variability in HIV
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envelope glycoproteins
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3 subgroups of HIV-1
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M (major), O (outlier), and N (neither M nor O)
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most common HIV-1 in US
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M-B (M divided into A through K)
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how does HIV infect cells
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uses CD4 molecule as receptor and various chemokine receptors as coreceptors
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is binding to CD4 sufficient for infection of HIV
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no, gp120 must also bind to other cell surface molecules for entry (especially CCR5 and CXCR4)
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M-tropic type of HIV uses what coreceptors
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aka R5, uses CCR5; predominant in early infection until T viruses gradually accumulate
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initial step of infection with HIV
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binding of gp120 envelope glycoprotein to CD4 molecules-leads to conformational change a formation of new recognition site on gp120 for coreptors CCR5 or CXCR4
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what occurs after binding of coreceptors
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conformational change in gp41 that results in exposure of hydrophobic region called fusion peptide at tip of gp41
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what is the fxn of the fusion peptide
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inserts into the cell membrane of target cells leading to fusion of virus with host cell
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resistance to HIV is due to
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homozygous with defective copies of CCR5; ~1% american population homozygous and 20% heterozygous
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what does HIV do in dividing T cells
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cDNA circularizes, enters nucleus, and is integrated into host genome
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APOBEC3G
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apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3; present in naïve T cells; HIV ineffective at infecting
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APOBEC3G fxn in association with HIV
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introduces cytosine-to-uracil mutations in viral DNA that is produced by reverse transcription; this inhibits further replication-mechanism not fully understood
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what occurs to APOBEC3G in activated T cells
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converts it into an inactive, high-molecular mass complex; Vif from HIV can bond and promote its degradation via cellular proteases
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NF-kB and HIV
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increased when T cells activated; relocates to nucleus and binds promotor regions of several genes; HIV genome also contain binding sites for NF-kB
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possible mechanisms by which HIV directly kills infected cells
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increased plasma membrane permeability associated with budding of virus particles and virus replication interfereing with protein synthesis
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what other factors lead to infected cell death by HIV
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progressive destruction of architecture and cellular composition of lymphoid tissues; chronic activation of uninfected cells or infections; loss of precursors of CD4+; fusion of infected and uninfected cells; CD8+ CTL killing
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reported immune deficits of HIV ppl before symptomatic
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reduced antigen-induced T-cell proliferation, decrease in Th1-type response relative to Th2 response; selective loss of memory subset Cd4+; and many more
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latent HIV infection
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infect CD4+ cells (T cells and macrophages); .05% resting CD4+ cells in lymph nodes infected-memory cells, so last months to years=persistent reservoir
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vpr HIV gene
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allows nuclear targeting of HOV preintegration complex through nuclear pore; this is how HIV infects and mulitplies in terminally differentiated nondividing macrophages
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Sources of HIV initiation and maintenance
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macrophages, dendritic cells
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dendritic cells and HIV initiation
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transport to regional lymph nodes where transmitted to CD4+; express lectin-like receptor that specifically binds HIV in an intact, infectious form
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B cells and HIV
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macrophages infected with HIV secrete IL-6 which stimulates proliferation; B-cell hyperplasia, hypergammaglobulinemia, formation of circulating immune complexes; yet, impaired humoral immunity, even T-cell independent processes
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neuro damage due to HIV
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thought to be from viral products and soluble factors produced by infected microglia (IL-1, TNF, IL-6; NO by gp41)
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when does seroconversion occur after HIV infection
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3-7 weeks due to antiviral humoral and cell-mediated immune responses
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what is likely responsible for initial containment of HIV infection
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HIV-specific CD8+ T cells; detected in blood about time of viral titer decline
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when does acute retroviral syndrome occur after HIV infection
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3-6 weeks and resolves spontaneously in 2-4 weeks
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3 CDC categories for HIV infection
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CD4+ levels above 500, btwn 200 and 500, and below 200 cells/ul
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elite controllers of HIV
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1% infected ppl; undetectable plasma virus 50-75 RNA copies/ml
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most common opportunistic infections with AIDS
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P jiroveci, Candida, CMV, mycobacteria (typical and atypical), crytococcus neoformans, toxoplasma gondii, cryptosporidium, herpes simplex, papovaviruses, and histoplasma capsulatum
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CMV in AIDS
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eye and GI, possible dissimination; retinitis with CD4+ <50
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cryptococcosis
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10% AIDS patients; meningitis
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Toxoplasma gondii and AIDS
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50% all mass lesions in CNS; causes encephalitis
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JC virus (papovavirus) and AIDS
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progressive multifocal leukoencephalopathy
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Herpes Simplex and HIV
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mucocutaneous ulcerations involving mouth, esophagus, external genitalia, and perianal region
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Persistant diarrhea in AIDS
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protozoans like cryptosporidium, isospora belli, microsporidia; also enteric bacteria like salmonella, shigella as well as M avium
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malignancy and HIV
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25-40% untreated dvlp; usually due to another virus-PPV, herpesvirus, EBV
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Kaposi sarcoma
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vascular tumor-proliferation of spindle-shaped cells that express markers of both endothelial and smooth muscle cells
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where do lesions of Kaposi sarcoma arise
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profusion of slitlike vascular spaces suggesting primitive mesenchymal precursors of vascular channels
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current KS pathogenesis model
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1) spindle cells produce pro-inflammatory and angiogenic factors which recruit inflammatory and neovascular components of the lesion 2) latter components supply signals that aid in spindle cell survival or growth
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virus associated with Kaposi sarcoma
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HHV8
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3 categories of AIDS-related lymphomas
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systemic, primary CNS, and body-cavity
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what does systemic lymphoma involve
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lymph nodes as well as extranodal, visceral sites; 80% all AIDS-related lymphomas
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most common extranodal sites in systemic lymphoma
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CNS most common extranodal site followed by GI
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evidence of EBV infection
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oral hairy leukoplakia (white projections on tongue)-result from EBV driven squamous cell proliferation
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risk of non-hodkins lymphoma
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120 fold increase with HIV infection; highest predisposing factor is CD4+<50
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long term toxicities of HAART
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lipoatrophy (facial fat), lipoaccumulation (deposition centrally), elevated lipids, insulin resistance, peripheral neuropathy, premature cardiovascular disease, kidney disease, hepatic dysfunction
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amyloidosis pathogenesis
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probably related to abnormal protein folding; immunologic abnormalities only associated with some forms
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what is amyloid
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pathologic proteinaceous substance deposited in extracellular space in various tissues/organs of the body in a wide variety of clinical settings
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amyloid appearance with light microscope and H&E stain
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amorphous, eosinophilic, hyaline, extracellular substance; encroaches on and produces P atrophy of adjacent cells
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amyloidosis
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group of diseases having a commonality of deposition of similar-appearing proteins
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electron microscopy of amyloid
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continuous, nonbranching fibrils with a diameter of ~7.5-10 nm
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X-ray crystalography and IR of amyloid
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cross-B-pleated sheet conformation (responsible for distinctive Congo red staining and birefringence)
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what makes up amyloid
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~95% fibril proteins; ~5% P component and other glycoproteins
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3 most common forms of amyloid proteins
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1) AL (amyloid light chains) 2) AA (amyloid-associated) 3) AB amyloid
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where are AL proteins derived
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derived from Ig light chains produced in plasma cells
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where are AA proteins derived
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unique non-Ig protein synthesized by liver; derived from proteolysis of SAAs from liver that is associated with HDLs
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where are AB amyloid proteins derived
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from B amyloid precursor protein and is found in cerebral lesions of Alzheimers disease
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what is AA amyloidosis associated with
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increased in inflammatory stated; often called secondary amyloidosis
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transthyretin (TTR)
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normal serum protein that binds and transports thyroxine and retinol; mutant form in genetic disorders = familial amyloid polyneuropathies
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B2-microglobulin
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component of MHC class I molecules and a normal serum protein; involved in amyloidosis on long-term hemodialysis
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how does serum amyloid P protein contribute to amyloid deposition
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stabilizes fibrils and decreases clearance
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categories of proteins that have inherent tendency to form amyloid
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1) normal proteins with tendency to fold improperly 2) mutant proteins that are prone to misfolding and aggregation
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categories of amyloidosis clinically
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primary-some immune disorder; seconard-chronic inflammation; hereditary or familial
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primary amyloidosis specs
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usually systemic and AL type; most common form; many have plasma cell dyscrasia
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multiple myeloma
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can cause primary amyloidosis in 5-15%-plasma cell tumor with multiple osteolytic lesions throughout skeletal system
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Bence-Jones protein
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light chains of Ig elaborated and found in serum
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reactive systemic amyloidosis specs
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systemic, composed of AA protein; complicated RA (~3%)and other CT disorders; IV drug users; non-immune tumore like renal cell carcinoma and Hodgkin lymphoma
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what used to cause reactive systemic amyloidosis b4 effective antimicrobial chemotherapy
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TB, bronchiectasis, and chronic osteomyelitis
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why do long term hemidialysis patients dvlp amyloidosis
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deposition of B2-macroglobulin since it can't be filtered through dialysis membranes; often present with carpal tunnel syndrome
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where do amyloid deposits occur with long term hemidialysis
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deposits in synovium, joints, or tendon sheaths
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familial Mediterranean fever
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autosomal recessive; autoinflammatory syndrome associated with abnormally high production of IL-1; attacks of fever accompanied by inflammation of serosal surfaces (peritoneum, pleura, synovial membranes)
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familial Mediterranean fever gene
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pyrin-one of a complex of proteins that regulate inflammatory rxns via production of pro-inflammatory cytokines
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what type of amyloid in familial Mediterranean fever
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AA proteins
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autosomal dominant amyloidosis generally due to
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mutant TTRs
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where are nodular deposits of amyloid most often encountered
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lung, larynx, skin, bladder, tongue, and region about eye
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what occurs around nodular amyloid
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infiltrates of lymphocytes and plasma cells in periphery
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amyloid in endocrine tissue
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tends to be derived from polypeptide hormones or unique proteins
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symptomatic presentation of senile cardiac amyloidosis
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restrictive cardiomyopathy and arrhythmias; amyloid composed of normal TTR molecule
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morphology of amyloid in affected organs
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often enlarged and firm, have waxy appearance
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congo red and amyloid
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pink-red color to amyloid deposits; green birefringence inder polarized light
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histo of amyloid in kidney
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amyloid in glomeruli, but peritubular tissue, arteries, and arterioles also affected
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progression of amyloid in kidney
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initially thickening of mesangial matrix with uneven widening of BM of glomerular capillaries; capillary narrowing and distortion of glomerular vascular tuft; capillary lumens obliterated
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amyloidosis of spleen (2 patterns)
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1) limited to splenic follicles (sago spleen) 2) walls of splenic sinuses and CT framework in red pulp (lardaceous spleen)
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amyloidosis of liver
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first in space of Disse, then encroaches on adjacent hepatic parenchymal cells and sinusoids; dissappearance of hepatocytes due to P = replacement of large areas of liver parenchyma
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heart and amyloidosis
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usually no significant changes on gross inspection; focal subendocardial accumulations and within myocardium btwn muscle fibers; expansion of myocardial deposits eventually causes P atrophy of myocardial fibers
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