Immunodeficiencies Flashcards
Asplenia increases susceptibility to
encapsulated bacteria
asplenic pt.s should be counseled to…
- receive vaccines for encapsulated bacteria
2. take antibiotics prophylactically in they begin to experience symptoms of respiratory infection
Dx of NK cell deficiency
flow cytometry
Viral susceptibilities with NK defects
varicella zoster
herpes virus
cytomegalovirus
epstein-barr virus
Bacterial susceptibilities with NK defects
mycobacterium (opportunistic pathogens)
fungal susceptibilities with NK defects
trichophytan
NEMO deficiency…
defect in protein IKKgamma required for NFkB–> leads to lack of expression of cytokine/chemokines and leads to increases susceptibility of infection
Defects in NFkB signaling affect which cell signaling path way
(INNATE SIGNALING PATHWAY)–> via TLR’S
Susceptibilities associated with NEMO
recurrent bacterial and viral infections
Tx for NEMO
bi-weekly injections of gamma globulin from a healthy donor; bone marrow transplant
LAD deficiency
defect in CD18 (subunit of LFA-1) that results in defective migration of phagocytes into tissues
LAD def. –> susceptible to
encapsulated bacteria
clinical indicator of LAD deficiency
delayed sloughing of umbilical cord
CGD is caused by
defective NADPH oxidase and inability to perform the oxidative burst–> cannot make toxic ROS’s
CGD leads to
chronic granuloma formation –> inability to kill phagocytosed bacteria
(chronic bacterial and fungal infections)
Glucose 6 phosphate dehydrogenase deficiency
defective G6-P leading to impaired oxidative burst–> very similar effects as CGD
MOP deficiency
inability to make HOCL–> ineffective bacteria killing
Chediak Higashi syndrome
defective vesicle fusion–> recurrent/ persistent bacterial infections and formation of granulomas
Neutropenia (basic definition)
low neutrophil count
susceptibilities with neutropenia
bacterial infections especially normal flora microbes
Cause of severe congenital Neutropenia (kostmann syndrome)
AR defects in GM-CSF or its receptor GM-CSFR
Cause of cyclic neutropenia
defect in the gene that encodes elastase (ELA-2)
this disease is cyclic every 2-4 weeks and alsts about a week
Neutropenia causes
elevated levels of ALL ANTIBODY ISOTYPES
*continued activation of B cells–> infections never really gets cleared
Primary immunodeficiencies with associated neutropenias
X linked hyper IgM
X linked agammaglobulinemia
WHIM syndrome
Griselli syndrome
In general defects in any of the compliment proteins will lead to?
susceptibility to extracellular bacteria
In general, defects in compliment regulatory proteins can cause? (2)
susceptibility to encapsulated bacteria (loss of C3)
or
autoimmune-like disease–> compliment destroys RBC’s via excessive MAC formation
Defects of components C5-C9 leads to susceptibility to
Neisseria
*no MAC formation
Deficiencies of C1, C2, C4
Immune complex disease–> small immune complexes created by antibody binding to its antigen is usually further opsonized by activation of the classical compliment cascade, promoting uptake and destruction of these small immune complexes
C3 defects lead to
susceptibility to encapsulated bacteria
Factor D, properdin factor P defects lead to what immune susceptibility?
susceptibility to encap. bacteria and Neisseria, but no immune complex disease
Factor I
reduced cleavage of C3b of C4b
*similar to C3 deficiency bc the result is depletion of C3
DAF and CD59 deficiencies lead to –>
paroxysmal nocturnal hemoglobulinemia
Paroxysmal Nocturnal Hemoglobulinemia is caused by
defects in GPI glycosylphosphatidylinositol
- DAF and CD59 cannot bind to host cell membrane and therefore cannot prevent the MAC from forming in the Host Cell–> RBC’s lyse
- a form of hemolytic anemia
CINH deficiency
HANE–> buildup of anaphylatoxins
MBL deficiency causes
inability to activate the lectin pathway ( a secreted PRR)–> leads to sever bacterial infections (acute phase response in hindered)
clinical presentation for MBL deficiency
pt.’s experience recurrent severe infections
C1 INH controls
spontaneous activation of C1 that always occurs–> w/o the inh. the system will constantly run and anaphylatoxins will buildup
Tc for C1inh defiiency
monthly injections of C1INH
a rare, acquired, potentially life-threatening disease characterized by complement-induced intravascular hemolytic anemia, red urine (due to hemoglobin in the urine), and thrombosis
Paroxysmal Nocturnal Hemoglobulinemia
CD59 and DAF requires
surface expression of GPI anchor
Tx for PNH
allogenic bone marrow transplantation is the only cure
*Compliment component C5 specific monoclonal Ab “eculizumab”–> aids in reducing thrombosis but is not curative
Inherited Antibody deficiencies
X-linked agammaglobulinemia (XLA) Pre-B Cell receptor (lambda 5) X-linked hyper IgM syndrome selective IgA selective IgG
Antibody deficiencies lead to…
susceptibility to extraceullular bacteria, especially encapsulated bug that are resistant to phagosytosis
Dx for Ab def.
monthly injections of gamma globulin from healthy donor
*all forms are susceptible to extracellular bateria and virions )unable to neutralize
XLA is cause by
X linked agammaglobulinemia
defect in B cell development
*defective BTK–> no signal transduction in the bone barrow–> improper B cell development/ B CELLS DONT SURVIVE BONE DEVELOPMENT
Do pt.s with XLA have a humoral immune system
HELL NAW
Pre-BCR (lambda 5) deficiency is from
mutation of lambda 5 gene (so chromosome 22)
–> non-functional surrogate light chain which result sin the inability of developiong B cells to produce a proper BCR–> they all undergo apoptotic death in germinal centers
X linked Hyper Igm is caused by?
defect in CD40 or CD40L or AID
defect in CD40L (defect in helper T cell function)–> results in
B cells and macrophages cannot receive the second signal of activation
AID deficiency results in
no isotype switching or somativ hypermutation
which is more desirable AID or CD40 deificiency
AID–> still be able to produce and activate effector T cells that could supply the second signal of activation
antibodies produced in some one with X linked hyper Igm syndrome
almost all of them will be IgM and the Igm levels will be lower than in some one who is immunocompetent
“Those individuals who cannot activate B cells will not have…”
germinal centers in secondary lymphoid tissues
Selective IgA deficiency cause?
unknown, likely heterogenous
Most pt.’s with Selective IgA are healthy until
exposed to parasite pathogens
People with Selecitve IgA deficiency are at risk of producing…
*they do not make any IgA
IgA-specific hypersensitivity fllowing blood transfusions
life threatening anaphylactic response
Selective IgG deficiency cause?
unknown, likely heterogenous
Most rare, yet important IgG deficiency
IgG1–> susceptible to many bacterial pathogens
* all subtypes of IgG can be deficienct
content of IgG circulating in adult blood that is IgG1
60-70%
*20-30% is IgG2
the most common immunodeficiency
Common Variable Immunodeficiency
common features of CVID
a group of 150 primary immunodeficiencies that have common features including:
HYPOGAMMAGLOBULINEMIA reduced ab levels (but all different etiologies)
clinical presentation of CVID
recurring infections mainly bacterial and/or viral pathogens involving ears, eyes, sinuses, nose bronchi, lungs skin, Gitracts, joints, bones, CNS, parotid glands etc
hypogammaglobulinemia means
low serum levels of gamma glonulins
* a subset of which is antibodies
CAUSES of CVID are usually ______ but do not appear until ______
genetic
2nd or 3rd gnerations of life
clinical triad for Ataxia telangiectasia
cerebellar defects (ataxia) spider angiomas (telengiectasia) IgA of IgE deficiency
prenatal finding associated with AT
elevated AFP
Cause of AT
inherited defect in ATM gene ( a gene that encodes DNA repair enzyme)
Ataxia Tangleictasia can result in….
B and T cell deficiencies
Low numbers if lymphocytes (especially T cells)
Very low levels of IgA and IgE (mostly IgA)
IL-12 signaling deficiency results in
inability to generate TH1 responses
inability to fully activate macrophages
IL-12 deficient pt.’s make much less
IFN gamma
Clinical presentation of IL-12 deficient pt.’s
recurrent susceptibility to disseminated mycobacterial infections
hyper IgE syndrome is also known as
Job’s Syndrome
What causes Job’s syndrome
genetic deficiency of STAT-3 function that results in reduced production of IFN gamma by TH1 cells and neutrophils that fail to respond to chemotactic signals
Two syndromes that cause
- very little IFN gamma production
- inability to activate TH1 responses
- IL-12 signaling deficiency
2. Hyper IgE/Job’s syndrome
Clinical findings of Job’s syndrome
- high Ige in blood
- eczema
- Recurrent abcesses with Staph aureus
- coarse facial features
FATED
facies, abcesses, retained primary teeth, IgE, Dermatologic problems
Hyper Ige polarizes immune responses toward
TH2 phenotype–> leads to increases IgE
Chronic mucocutaenous candidiasis Cause
T cell dysfunction, undefined cytokine deficiency
Clinical presentation of Chronic Mucocutaneous Candidiasis
persistent superficial infection of the skin, mucous membranes, and nails with candida organisms
CD8 dysfunction can be caused by
TAP transporter deficiency
CD8 alpha chain defect
Non-Sense mutation of perforin
TAP defects result in
*sometimes calles BARE LYMPHOCYTE SYNDROME (MHC CLASS 1)
low levels of MHC 1 molecules
defective responses to intracellular pathogens
VERY LOW NUMBER OF CD8 T CELLS BECAUSE FEW ARE POSITIVELY SELECTED IN THYMIC DEVELOPMENT
CD8 ALPHA CHAIN DEFECT
SAME PHENOTYPE AS TAP DEFECTS
*HIGHLY SUSCEPTIBLE TO INTRACELLULAR BACTERIA
non-sense mutation of perforin causes
- dramatically or totally reduced CTL activity
- pt.’s have NORMAL numbers of CD8 t cells
- CTL’s are unable to induce programmed cell death
Perforin mutations also affect which cell type
NK cells
Defect in CD4 T cell function can result in______
SCID phenotype
* b cell responses require an effector t cell for activation
CD4 t cells are important to ____ mediate and _____ mediate immune responses
antibody
cell-mediated
Bare Lymphocyte Syndrome (SCID)
lack of expression of MHC II
*unable to mount cd4 responses or B cell responses
Wiskott-Aldrich Syndrome (WAS)
SCID PHENOTYPE
defect in cytoskeletal reorganization that is required for T cells to deliver cytokines and other signals to B cells and macrophages
causes cell-crosstalk deficiency
Wiskott-Aldrich Syndrome
Adenosine Deaminase or Purine nucleotide phosphorylase deficiency both result in (SCID)
accumulation of toxic nucleotide catabolites that kills all lymphocytes during their development
COmmon Gamma chain deficiency results in
SCID
FAILURE OF T CELLS TO PROLIFERATE NO T CELLS OR B CELLS -->Gamma chain is signaling component of IL2, 4, 7, 9, 15 --> gamma chain interacts with JAK3
JAK 3 DEFICIENCY
FAILURE OF T CELLS TO PROLIFERATE NO T CELLS OR B CELLS -->Gamma chain is signaling component of IL2, 4, 7, 9, 15 --> nteracts with GAMMA CHAIN
T CELL GROWTH FACTOR
IL2
B CELL GROWTH FACTOR
IL7
CD3 DEFICIENCY RESULTS IN
SCID
no CD4+ or CD8+ T cells; no T cell function:.
CD3 DEFICIENCY CAN RESULT FROM
nonfunctional CD3 delta, epsilon, or zeta chain
DiGeorge syndrome results from
small deletion in chromosome 22 (q11.2
Characteristics of Digeorge syndrome
SCID
congenital heart disease (40%), palatal abnormalities (50%), learning disabilities (90%), hypocalcemia (50%), mild differences in facial features
complete digeorge syndrome (SCID)
athymic
*very few t cells if any
Tx for digeorge synrome
thymic transplant, no tx for other features
ZAP 70 deficiency (SCID)
pt.’s have absence of CD8 T cells, but normal number of NON-FUNCTIONAL CD4 t cells
Cause of Zap 70 def.
genetic defect that prevents expression of function zap70
what is zap 70
tyrosine kinase that associates with phosphorylated ITAMs during t cells development
*ZAP 70 is required for signaling via the TCR
Tx for ZAP-70 deficiencty
bone marrow transplant
Cause of OMENN syndrome
mis-sense muatation that results in partially active RAG enzymes
result of OMENN syndrome (SCID)
absence of B cells and low numbers of oligoclonal autoreactive T cells
*susceptible to all types of infections and also suffer from autoimmune disease that attacks skin and GI as well
tx for OMENN syndrome
bone marrow transplant
SYMPTOMS OF OMENN SYNDROME
erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)
a genetic deficiency of (AIRE) that is expressed in the thymic medulla
*impaired negative selection of thymocytes
Clinical presentation of APECED
problems in numerous glands (polyglandular) including hypoparathyroidism, hypogonadism (with sex gland failure), adrenal insufficiency, type 1 (insulin-dependent) diabetes, and latent hypothyroidism, total baldness (alopecia totalis), keratoconjunctivitis, tooth enamel hypoplasia, candidiasis (yeast infection), juvenile-onset pernicious anemia, gastrointestinal problems (malabsorption, diarrhea)
transcription factor that regulates expression of several hundred host-tissue specific genes by epithelial cells in the thymic medulla
AIRE
Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX) results from
deficiency of FoxP3 expression by Tregs
*early onset autoimmunity to a variety of host tissues due to lack of Treg cell function
Clinical triad associated with IPEX
1) watery diarrhea,
2) eczematous dermatitis
3) endocrinopathy (type 1 diabetes)
Tx for IPEX
aggressive immunosuppresion and/or bone marrrow transplant
Autoimmune Lymphoproliferative Syndrome (ALPS) is characterized primarily by what physical findings
lymphadenopathy and splenomegaly
What causes ALPS
Autoimmune Lymphoproliferative Syndrome
*mutation in Fas, FasL, or Caspase 10
immune cells failing to undergo apoptotic death following an immune response; causes overpopulation of secondary lymphoid tissues
PRESENTATION OF ALPS
Autoimmune Lymphoproliferative Syndrome
autoimmune hemolytic anemia and neutropenia, thrombocytopenia (decreased platelets in the blood), lymphadenopathy, splenomegaly; also, often have large number of CD4- CD8- T cells
TX OF ALPS
Autoimmune Lymphoproliferative Syndrome
IMMUNOSUPRESSION
IV-Ig
Classical presentation of DiGeorge syndrome
*CATCH 22* Cardiac Abnormality (especially tetralogy of Fallot) Abnormal facies Thymic aplasia Cleft palate Hypocalcemia/Hypoparathyroidism. 22ND chromosome
