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148 Cards in this Set

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