immuno: primary and secondary immune deficiencies Flashcards Preview

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Flashcards in immuno: primary and secondary immune deficiencies Deck (53):

primary immunodeficencies (congenital, less common)

IgA (1:700)
hereditary angioedema (1:1000)
DiGeorge syndrome (1:3000)
common variable hypogammaglobulineima (1:70,000)
SCID (1:100,000)
X-linked agammaglobulinemia (1:200,000)


causes of secondary (induced) imm. defs

*malnourishment*(world), neoplasia, med interventions*(US): chemo, irradiation, NSAIDs, anti-rheums, cortsters


immunodeficiencies charac. by..

inc., persistent, and/or recurrent infections
and by unusual orgs (opportunistic pathogens)


phagocytic deficiencies from infections w.

EC pathogens, "opportunists"
S. aureus, S. pneumo, E. coli, Pseudomonas
fungi: candida, Aspergillus


quantitative neutrophil deficiencies: neutropenias

det. by absolute neutrophil count, lower ANC, higher inf. risk (inc. if neutropenia persists >3 days)
NR: 2-6000/mm3
mild: 1-1500 mod: 500-1000 sev:


quantitative defs: primary neutrophil deficiency (congenital agranulocytosis, Kostmann's syndrome)
gene assoc.??

almost complete absence mature blood neutros (Abs/granulo transfusions help but eventually succumb
50% ELANE gene (chrom 19)
15% HAX1 gene (chrom 1)
G-CSF, BM transplants


new congenital neutrophil defect syndrome w. homozygous mutations in gene

neutropenia, neutro dysfunction, nephromegaly


secondary (radiation/chemo induced) neutropenia

also specifically in this ca??

use of ??? allows neutrophil count recovery

??? predominate in a neutropenic pt


??? : Abs that attack neutrophils
??? : transient/temp. neutropenia following certain infections

autoimmune neutropenia
cyclical neutropenia (freq: 10^-5, unknown etio)


qualitative neutrophil deficiencies

defects in phagocytosis process that limits defense mech


leukocyte adherence deficiency (LAD)
what integrins?

what is defective/deficient?

how does this limit the leuko?

autosomal recessive prim. immdef
mediated by selectins and integrins: CD11a/CD18 and CD11b/CD18
Beta chain of CD18 in LAD1 (chrom. 1) and selectin ligands deficient in LAD2
unable to adhere to endo cells-->inhib. extravasation into extravasc. tissue


LAD consequences ??

also affects nonphagos, how?

recurrent bac infections w. abnormal inflammatory reactions and inability to form pus i.e. ST inf, periodontitis
impairs CTL and NK adherence to target cells and Th2 and B cells to form conjugates needed for T cell med B cell help


LAD individuals: lasting consequences ??

impaired wound healing
allogeneic stem cell transplant (cure)


chemotactic defects: lazy leukocyte syndrom

chemotactic signals involved??
manifests similar to ?? cure is ???

defect in neutrophil's response to chemotactic signals, or deficiency in production of those factors:
C3a, C5a, chemokines or chemokine receptors
LAD, cure is allogeneic stem cell transplant


killing defects: chronic granulomatous disease (CGD)
manifests in who??

most prevalent primary defect in IC killing of ing. bac
boys in first 2 yrs, X-linked recessive
disseminated granulomatous lesions in various organs-->dies of septicemia by 6,7


CGD genetic defect

cytochrome b and NADPH oxidase
also G6PD and myeloperoxidase-->can't produce H2O2 during phago-->allows survival of catalase-producing bac (S. aureus)
acts as "Trojan horse": transports pathogen around


CGD tx

what manifests like CGD ???

Actimmune (recombinant IFN-y), BM transplant usually req.

myeloperoxidase deficiency


Chediak-Higashi Syndrome
mutation where ??

autosomal recessive, phago killing defect
mutation in LYST gene on chrom. 1 (1q42.1-q42.2)
encodes protein for microtublule polymerization
w.out: defect in lysozome generation in function
neutros defective in IC killing and CTLs defective in making lysozomes w. granules and perforins


pts w. Ched-Hig Synd present with ??? in cytoplasm
manifest with ??
unusual appearance?
cure ??

granulocytes and platelets w. giant granules
recurrent pyogenic infections (Staph, Strep)
may have silver hair and light colored eyes
BM transplant, can use abx to fight off inf


quantitative humoral immune deficiency: Bruton's X-linked agammaglobulinemia
affects who ?? how ??
what specific bac ??

primary deficiency, level of passively act. maternal IgG declines (6 mos age)
male infants-->severe recurrent bac inf (strep, staph, h. flu) and others that produce anti-phago capsules


Bruton's X-linked agammaglobulinemia: pts lack ??

defect in ??? gene

have how much circulating immglobulin ??
does not protect from ??? why ??

pts have normal pre-B cell levels, lack mature B cells and plasma cells
defect in BTK gene, involved in B cell rec. cytoplasmic signaling
0-20% normal levels of circ. Igs
gamma globulin (HISG) to protect from bac infections
not much for sinus/pulm/intestinal bac infections, can't get to mucosal sites


qualitative humoral immune deficiency: X-linked hyper-IgM syndrome
mutation in ???

low, no IgG, E, A but elevated IgM

mutation to CD40 ligand gene: on surface of T helper cells, norm. binds to CD40 and initiates B cell prolif, isotope switch and germinal center formation


X-linked hyper-IgM syndrome pts also have ???

typ. present with ???

autoAbs against neutrophils, platelets, RBCs (*note before transfusing!*)
pyogenic infections w. staph, strep
OM, septicemia, pneumonia


qualitative humoral immdef: IgA deficiency
present with ???

this is more common in these pts ??
may also have ??

*most common isotype def.* 1/600-800 ppl
GI/resp infections, sev. allergies; inc. penetration of allergens at mucosal surfaces-->IgE stimulation
AI disease: lupus, celiac
Abs agains IgA (*dangerous when infusing plasma!!*)


common variable immunodeficiency (qual. humoral)

defects in ???

present with ??? how old ???

normal levels mature B cells, defect in maturation to functional plasma cells
defects in cytokine rec. expression and Th2 cytokine prod. (IL-5)

present w. resp. inf., 20-40 yo
HISG (gamma globulin) to protect from bac inf


B or T cell deficiencies more severe?
assoc. with...??

T cell: impact both humoral and CMI
inc. susceptibility to viral protozoan, fungal, and opportunistic infections (virus, Mycobacteria, Candida, Pneumocystis) *IC pathos*


quant. primary T cell deficiency: DiGeorge syndrome
(congenital thymic aplasia)

genetic deletion ??

dev. of 3rd, 4th pharyngeal pouches 10-12 wks gest-->abnormal thymic dev (some complete athymia), hypoPTH, CV, facial anomalies

deletions in chromosome 22 (22q11.2 region)


DiGeorge presentation

tests ??

if complete athymia, req ???

repeated viral, fungal, protozoan infections with v. low T cell CD3+ counts
no/low DTH rxn to skin test Ags, dec. response leukocytes to T cell mitogens (PHA and ConA), dec. MLR rxns
thymus transplant (or die around 2)


quant. primary T cell deficiency: ZAP70 Deficiency


present with ?? why can't fight off??

only cure ??

Zeta assoc. protein: tyrosine kinase critical for signalling thru T cell rec
autosomal recessive: inherit 2 mutated genes

opportunistic inf. loss of CD8+ T cells, presence of non-func CD4+ (can't signal thru TCR)
BM transplant


qual. primary T cell deficiency: Chronic Mucutaneous Candidiasis
two genetic forms ??

present with ???
tx ??

heterogenous group, chronic C. albicans infections
autosomal dominant form: mutations in STAT1
recessive form: mut. in AIRE
def. in T cell ABILITY to respond spec. to candida
skin, nails, mucous mem infections (not disseminated)
anti-fungals, and tx for CMI restoration


qual. primary T cell def: Job syndrome (hyper IgE)

autosomal dominant
defect in STAT3 gene (chrom. 17q21.31)
failure of CD4+ T cells to become Th17 cells


Job syndrome presentation

high levels IgE, eczema, recurrent inf. with Staph, Candida, abcesses, pneumonia, retained primary teeth, tissue and blood eosinophilia


AIDS (secondary T cell immunodeficiency) mech

HIV infects cells w. CD4 marker: T cells and dendritic macros


hallmarks of AIDS: latent infection

+HIV: HIV p24 Ag or Abs, ELISA and western blot +
no s/s, normal CD4+ count (>10^3/mm3)


hallmarks of AIDS: progression
"pre-AIDs"/ARC symptoms ???
besides low CD4+ see these labs ???

progressive reduction in CD4+ T cells btw 200-500/mm3
FUOs, wl, diarrhea, LAD, fatigue, night sweats


in progressing AIDS, besides low CD4+ see these labs ??

leukopenia, thrombocytopenia, anemia, hypergammaglobulinemia w. polyclonal Ab prod but loss of sp. Ag responsiveness (no one controlling B cells! (dec. Tregs) but unfocused actions)
dec. response to mitogens
dec. skin test responsiveness (anergy): CMI measure (Ags from Candida, Trichophyton, tetanus, mumps, PPD)


AIDS (full-blown)



most common OIs in AIDS pts

oral thrush: Candida
chronic or exacerbated oral, ana, genital HSV
Pneumocystix carinnii pneumonia (PCP, about 50% AIDs pts!)
typical and atypical TB


death in AIDS pts when CD4+ falls below..



combined humoral and CMI defs: reticular dysgenesis

rare, fatal congenital def.
goth myeloid and lymphoid stem cells fail to differentiate during hematopoiesis-->NO B cells, T cells, or neutros!
death after birth


combined humoral and CMI defs: bare lymphocyte syndrome, 2 types:

labs ??

presentation ??


Type I: no HLA class I expression
Type II: no HLA class I OR II expression
faulty AG presentation to T cells-->no act. T cells develop
affects all adaptive IR
lymphopenia, low T cell # and Ag-sp T cell tests (DTH, MLR) BUT NORMAL mitogen responsiveness
recurrent bac, viral, fungal infections (OIs)
manifests like AIDS
die before 5 unless BM transplant


comb hum/CMI def: SCID: severe comb. immunodeficiency

40-50% caused by this genetic mutation

depressed B and T cell counts, inc. susc. to infections, wasting, FTT
"bubble baby syndrome": def. T-dep Abs and CMI
mutation of IL2RG gene on X chrom (XSCID) codes for gamma chain on cytokine receptors: IL-2r, IL-4r, IL-7r
-do not initiate cytoplasmic signaling/activation when bind


20% of SCID cases caused by this genetic mutation

ADA gene on chromosome 20--> adenosine deaminase: toxic accumulation of metabolites-->loss of B and T cells


SCID lab tests ??
CXR ??
presentation ???

tx ??

quant/qual depression B and T cells
thymic shadow absent on CXR
constant diarrhea, FTT, thrush, recur. bac, viral, fungal, protozoan inf
HLA-matched BM transplants


OMENN syndrome
mutations ?
what's produced ??

presentation ??
tx ??

autosomal recessive form of SCID
mutations in RAG1 and/or RAG2 gene (chrom 11)
no B cells produced, a few T cell clones (auto reactive, excessive)
LAD, eosinophilia, hepsplenmeg
BM transplant


comb. hum/CMI def: Wiskott-Aldrich syndrome
mutation ??

occurs when, severity ??
presentation ??

labs ??
up to 1/3rd develop ??

X linked, mutation of gene encoding WASP protein-->cytoskel. reorganization for T cell act. of B cells and macros
impacts lymphos and platelet function
childhood disease, less sev. than SCID
recurring OIs, resp. inf
NORMAL number T, B cells
eczema, def. Ab prod (esp. against carb Ags), thrombocytopenia, small platelets
gamma globulin injections (Ab replacement), BM transplant
AI disease, lymphomas


comb. hum/CMI def: Ataxia-Telangiectasia
mutation ??

at risk for ??

autosomal recessive
ATM gene on chrom. 11-->repair of dsDNA breaks
low B and T cells (ds breaks happen during dev.)
B cells struggle to switch classes, esp. to IgA
lung inf., inc. risk of leukemia, lymphoma
other organ systems involved (neurological)


complement deficiencies

affected functions:
Ab (class. compl pathway lysis) and phagocytes (opsonization)


deficient in early classic complement components

present with ??

C1q, Cqr, C1s, C2, C4

inc. IC disease or rheumatic disease (dec. IC clearance) due to failure to gen. C3b

recurrent inf. w. EC pyogenic bac (staph, strep) due to failure to gen opsonins


C3 deficiency manifests w.

recurrent EC encapsulated bac inf. and failure to clear ICs-->rheumatic disease


alternative pathway deficiencies

Factor B, D, H Properdine
inc. incidence of Neisseria, meningococcal inf


MAC complement components deficiency

C5, C6, C7, C8
recurrent/disseminated inf w. Neisseria meningitidis and N. gonorrhoeae


Complement regulatory component deficiencies: hereditary angioedema


defect in C1 inhibitor (chrom. 11):
also reg. Hagemann factor activation and kinin and fibrinolytic system
overprod. of peptides that reg. vasc perm-->fluid leak from vasculature into tissue space
purified C1INH

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