Primary Immunodeficiencies Flashcards
Primary immunodeficiencies
congenital defect: present at ~birth, perinatally, sometimes asymptomatic
NOT caused by damage to immune system
Almost always a genetic defect (spontaneous or inherited)
Consequences:
Absence or dysfn of a molecular component of the immune system
Variable phenotype
Primary immunodeficiency associated with infections (but not always)
recurrant
early age (usually)
mult sites
mult pathogens, including some normally avirulent
80% decrease Ig
Inheritence of X linked primary ID diseases
Disease penetrance
male gender: hemizygosity- risk factor for inherited PIDs
Female gender- random X chromosome inactivation- preferential survival of cells carrying non mutant genes
Bruton’s (B cell) tyrosine kinase (Btk)
disease info
X linked gene- only males manifest. Recurrant infections, esp repiratory. Reduced LNs.
phenotype variable
Common pathogend encapsulated bacteria and enteroviruses- can not opsonize and thus have a harder time phagocytizing
All serum Igs significantly reduced
b cells significantly reduced or absent
Where Brutons tyrosine kinase works
For survival, Pre-B cell requires:
Successfully rearranges H chain
association with surrogate light chain
association with Ig signaling molecules
If Btk not there, you can not get to immature B and your B cells will die.
Btk has to be expressed under preB cell receptor for maturation to progress
Hyper-IgM syndromes (HIM)
Info
refcurrant pyogenic infections
neutropenia, autoimmine hemolytic anemia, thrombocytopnia
Liver sz
Normal or elevated serum IgM, decreased or absent IgG, IgA, IgE
B cells substantially decreased
Hyper IgM 1
Mutation in CD40L
Expressed on T cell
x linked
Weak T / B interaction: defective somatic mutation defective class switching absent germinal center formation
Defective T cell/ macrophage interaction:
defective cell medited immunity
Hyper IgM 3
Autosomal
Defect in CD40
expressed on DCs and B cells
Weak T / B interaction: defective somatic mutation defective class switching absent germinal center formation
Defective T cell/ macrophage interaction:
defective cell medited immunity
Hyper IgM syndome 2
Mutation in activation induced deaminase (AID)
(helps in B cell clonal expansion)
Failure of IgM class switching and somatic mutation
low affinity antibodies and you really only have IgM. Not good.
SCID
Severe combined immunodeficiency diseases
fatal
both T and B cells affected (B cell deficiency may be 2* to T cell defect, in which case “severe” is not used)
recurrant fungal, bacterialm and viral infections
heterogenous genetic defects
50-70% of SCIDs: reduced or absent T and B cells and Ig; NK cells predominant lymphocyte
30-50% reduced or absent T fcells only with normal B cell numbers
SCID
Mutations in T cell signaling
IL-2Ralpha chain, IL-7Ralpha chain, common gamma chain, JAK3
Jak3 -> IL-7R, IL2R, IL4R
IL-7R- cell engages this after VDJ beta chain. when cell engages this allows cells to divide several times. Dont get that division if IL7R not there. Problem with T cell expansion.
defective T cell development (in hte absence of IL-7 derived signals)
Defective peripheral T cell expansion
Normal or increased B cells; reduced serum Ig
Autosomal recessive SCID
Mutations in RAG1 or RAG2
cleavage defect during V(D)J recomb
decreased or absence of T and B cells, reduced serum Ig
Autosomal recessive SCID
Mutations in artemis
failure to resolve hairpins suring V(D)J recomb: junctional diversity defect
decreased or absenve of T and B cells ; reduved serum Ig
Autosomal SCID
DeGeorge
22q11.2
abnormal embryonic development of 3rd and 4th pharyngeal arches- critical for developing thymus
rudimentary or absent thymus
Decreased T cells, normal B cells; normal or reduced serum Ig
Problems in class switching and hypermutation
Autosomal recessive SCID
Mutations in adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP)
defects in nucleotide salvage pathway.
defect in ADA or PNP leads to increase in adenosine, deoxyadenosine, dATP, dGTP
this is not toxic to normal cells but is toxic to lymphocytes
leads to a progressie decrease in T, B, and NK cells over the first decade of life
Autosomal recessive SCID
mutations in transcription factors required for MHC class II expression or induction
Bare lymphocyte syndromes (defective MHC class II expression)
can not make MHC class II
Defective lhymopoisis of CD4+ T cells
Defective Ab response because B calls cant get T help
Defective cell mediated immunity
Autosomal recessive SCID
mutations in TAP-1, TAP2, or tapasin
MHC class I deficiency.
Reduced or inactive CD8
Autosomal recessive SCID
Mutations in CD3+ (epsilon or gamma chains) or ZAP-70
Defectove T cell signaling through TCR with normal T cell levels
Leads to defects in cell mediated immunity
defects in antibody production
Wiskott-Aldrich Syndrome
X liked SCID
Protein expressed in all hemopoetic cells
defects in platelets
get petichia, bruising, ezcema, severe heomorrhage
recurrant bacterial infections (exp polysaccharide capsules)
Splenomegaly common
decreased WAS prottein which is x linked
normal B cell numbers, progressive T cell decrease
IgM reduces (T independent responses) IgA and IgE elevated
Thrombocytopnia
Neutropnia in severe form of WAS
Wiskott-Aldrich Syndome
WAS protein
dominate initiatior or actin nucleation and fiber elongation
important in actin branching and polymerization
cell to cell interaction is relient on actin filaments
Wiskott-Aldrich Syndrome Consequence
Impaired cell signaling signaling in T and B cells
Absent B cell responses to T independent antigens
blunted antigen speciffic T cell responses
Defective polarization, motility, and phagocutosis in neutrophils and macrophage
Mutations in AIRE
AIRE- autoimmune regulator. Induces selection of select proteins from the periphery in the thymus
Failure of central T cell tolerance to some peripheral self antigens
Autiummone polydocrinopathy syndrome (APS) with candidiasis and ectogermal dystrophy (APECED)
Mutations in FoxP3
X linked
TF critical for Treg production
Normal immunosuppression (inhibit T cell activation) by Treg cells
Failure of central and peripheral T cell tolerance
Immunodysregultion polyendocrinopathy enteropathy X linked syndrome IPEX- often have colitis- effector t cells must be actively downregulated but if you dont downregulate you get inflammatory bowel dxs
Mutations in pagocyte oxidase complex (NADPH oxidase)
Chronic granulomatous disease
X linked
spontaneously made when phagocyte ingests foreign material. Phagosome fuses with lysosome. Initiates making of this fcomplex. GP91 is one of these proteins.
Defective GP91 means cant assemble the complex
ROS and NO do not get produced
compromiosed destruction of microbes in phagolysosome
DEFEVCTIVE PRODUCTION OF ROS -> DEFECTIVE KILLING OF PHAGOCYTIXED BACTERIA -> CHRONIC T CELL STIMULATION OF MACROPHAGE -> GRANULOMA FORMATION
Leukocyte adhesion deficiencies (LAD)
Required steps for neutrophil transmigration from blood vessels tp the surrounding tissue
1) leukocyte rolling- selectin mediated loose adhesion to vessel wall (LAD2)
2) leukoccyte activation- integrin actication and conformational change (LAD3)
3) leukocute firm adhesion- activated integrins mediate firm binding to the vessel wall (LAD1)
4) leukocyte transmigration- leukocytes migrate between endothelial cells and exit the vasculature
LAD-1
Beta2 integrins (CD18, LFA-1, Mac-1) deficiency
Failure of neutrophil recruitment to site of infection
deficient T cell/APC interactions
LAD-2
E and P selectin ligands (CD62) deficiency
Failure of neutrophil recruitment to site of infection
LAD-3
kindlin 3 deficiency: decreased integrin activation
Failure of neutrophil recruitment to site of infection
Relative occurance of primary immunodeficiency diseases
Ab the most
combined B and T cell deficiencies
phagocytic deficiencies
cellular (t cell)
complement/ other innate
Case: M with hx several ear, sinus, and skin infections in first few years. Hosp for bacterial PNA. At 2.5 developed cough with sputum and T. Poor abx response. Pain and swelling L elbow.
CXR: c/w PNA
CBC: elevated neutrophils, normal lymphocyte levels
Elbow fluid asperate revealed numerous neutrophils and gram - coccobacilla
Serum Ig: very low levels IgG, IgA, IgM
Flow cytometry revealed complete absence of CD19+ B lymphocytes
B cell immunodeficiency due to Btk mutation
Required for B cell maturation past pre-B cell
Case: M born full term developed atopic dermatitis after birth. Ped thought just ezcema- gave hydrocortizone cream to control itching
at 4 mo, he developed intractible watery D. Now had fallen under weight percentile
Clinic 6mos: Nornal WBC, hemoglobin, and platelets
eosinophils elevated, IgE elevated
Blood glucose was high, glucose in urine
Autoanitbodies against pancreatic islets found -> IDDM
Duodenal biopsy: almost total villous atrophy with dense plasma and T cell atrophy
had brother with death young due to severe D and low platelet count
Absence of FoxP3+ T cells
IPEX syndrome (defective Tregs)
immunodysregulation polyendocrinopathy enterophathy X linked syndrome
IPEX sx
intractable watery D, leading to failure to thrive, dermatitis, and autoimmune DM in infanfcy
D is due to widespread inflammatin in the gut, including th colon that results in villous atrophy- failure of immunsuppression to environmental (microbial) antigens
Other features of IPEX syndrome include autoimmune thrombocytopnia, neutropenia, anemia, hepatitis, nephritis, hyperthyroidism, or hypothyroidism, food allergies
2 year old M with hx recurrant resp infections, ezcema, asthma, and episodes of bloody D. Ezcema occasionally became infected with staph and petechia appeared on skin. Frequent otitis media and resp infections, including PNA
CBC diff normal except low platelet count and sizeLoq IgG, low IgM, high IgA, high IgE
had low specific Ab titers to vaccines
normal numbers B, T, and NK cells
T cell responses to mitogen stimulation blunted
Wiskott- Aldrich Syndrome
WAS protein defect: defective signal transduction rom cell membranes to cytoskeleton in all lymphoid cells as well as platelet abnormalities
WASP?
Wiskott Aldrich Syndrome
Widespread deficiencies in cellular and humoral immunity
key feat:
thrombocytopnia with small platelets
low IgM, IgG
Elevated IgA, IgE
diminished ab responses to polysaccharide antogens and isohemagglutinins -> compromised T and B cell response
T cell lumphopenia and decreased mitogen proliferation may be present
Pts have recurrant bacterial sinopulmonary and invasive (meningitis, sepsis) infections with encapsulated bacteria. Viral infections (HSV, molluscum) and opportunistic infections (pneumocystis joroveci PNA, candida) can also occur
32 year old F presents with hx 6 sinus infections and 2 PNAs over the past 2 years. The last episode of strep PNA required tx in the hosp with IV abx
As a child she had frequent otitis, sinuitis, and tonsillitis. When she was 34 she was dxed with thyroid insufficiency and placed on thyroid hormone replacement therapy. She also has a past hx ITP (idiopathic thrombocytopenia purpura)
enlarged spleen appreciated
Low IgG, low IgA, normal IgM
Low CD19+ B cells and there were predominately naive (IgD+,IgM+)
specific vaccine responses all low
elevated anti thyroid abs
Sister died at 32. recurrant bacterial infections, helolytic anemia, vasculitis, Gi cancer
Mother died of non-hidgekins lymphoma
Common variable immunodeficiency
Genetic analysis showed complete deletion of exon 2 in the ICOS (inducible T cell costimulator) fene whic his expressed on activated T cells
ICOS deficiency results in compromised T cell activation and reduced helper cell for B cell maturation to plasma cells and memory B cells
autoimmune dz occurs in 50% of ppl with CVID, perhaps due to deficiency in adaptive Treg cells
F 6 week old pt. Umbilical cord has continued to ooze nonpurulent flud and has failed to completely dye. SHe haws had a 38.5* T
Born at full term and weighted 3.7kg. Well with excellent growth
Inflamed skin around umbilical stump showed e coli and staph aureus
WBC count high with high neutrophils
Normal IgG, IgM, IgA
greatly reduced CD18 (LFA-1) expression on WBCs
Leukocute adhesion deficiency
mutation in integrin CD18
DX: LAD-1: Absent LFA1 (CD18)
deficiencies in LFA-1 prevents neutrophils from adhering to ICAM-1 on activated endothelium, resulting in failure to be recruited to site of infection
