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FMS Week 10 > Primary Immunodeficiencies > Flashcards

Primary Immunodeficiencies Flashcards

1
Q

Primary immunodeficiencies

A

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

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2
Q

Primary immunodeficiency associated with infections (but not always)

A

recurrant

early age (usually)

mult sites

mult pathogens, including some normally avirulent

80% decrease Ig

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3
Q

Inheritence of X linked primary ID diseases

Disease penetrance

A

male gender: hemizygosity- risk factor for inherited PIDs

Female gender- random X chromosome inactivation- preferential survival of cells carrying non mutant genes

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4
Q

Bruton’s (B cell) tyrosine kinase (Btk)

disease info

A

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

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5
Q

Where Brutons tyrosine kinase works

A

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

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6
Q

Hyper-IgM syndromes (HIM)

Info

A

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

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7
Q

Hyper IgM 1

A

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

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8
Q

Hyper IgM 3

A

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

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9
Q

Hyper IgM syndome 2

A

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.

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10
Q

SCID

Severe combined immunodeficiency diseases

A

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

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11
Q

SCID

Mutations in T cell signaling

A

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

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12
Q

Autosomal recessive SCID

Mutations in RAG1 or RAG2

A

cleavage defect during V(D)J recomb

decreased or absence of T and B cells, reduced serum Ig

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13
Q

Autosomal recessive SCID

Mutations in artemis

A

failure to resolve hairpins suring V(D)J recomb: junctional diversity defect

decreased or absenve of T and B cells ; reduved serum Ig

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14
Q

Autosomal SCID

DeGeorge

A

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

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15
Q

Autosomal recessive SCID

Mutations in adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP)

A

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

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16
Q

Autosomal recessive SCID

mutations in transcription factors required for MHC class II expression or induction

Bare lymphocyte syndromes (defective MHC class II expression)

A

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

17
Q

Autosomal recessive SCID

mutations in TAP-1, TAP2, or tapasin

A

MHC class I deficiency.

Reduced or inactive CD8

18
Q

Autosomal recessive SCID

A

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

19
Q

Wiskott-Aldrich Syndrome

X liked SCID

A

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

20
Q

Wiskott-Aldrich Syndome

WAS protein

A

dominate initiatior or actin nucleation and fiber elongation

important in actin branching and polymerization

cell to cell interaction is relient on actin filaments

21
Q

Wiskott-Aldrich Syndrome Consequence

A

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

22
Q

Mutations in AIRE

A

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)

23
Q

Mutations in FoxP3

A

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

24
Q

Mutations in pagocyte oxidase complex (NADPH oxidase)

A

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

25
Q

Leukocyte adhesion deficiencies (LAD)

Required steps for neutrophil transmigration from blood vessels tp the surrounding tissue

A

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

26
Q

LAD-1

A

Beta2 integrins (CD18, LFA-1, Mac-1) deficiency

Failure of neutrophil recruitment to site of infection

deficient T cell/APC interactions

27
Q

LAD-2

A

E and P selectin ligands (CD62) deficiency

Failure of neutrophil recruitment to site of infection

28
Q

LAD-3

A

kindlin 3 deficiency: decreased integrin activation

Failure of neutrophil recruitment to site of infection

29
Q

Relative occurance of primary immunodeficiency diseases

A

Ab the most

combined B and T cell deficiencies

phagocytic deficiencies

cellular (t cell)

complement/ other innate

30
Q

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

A

B cell immunodeficiency due to Btk mutation

Required for B cell maturation past pre-B cell

31
Q

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

A

IPEX syndrome (defective Tregs)

immunodysregulation polyendocrinopathy enterophathy X linked syndrome

32
Q

IPEX sx

A

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

33
Q

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

A

Wiskott- Aldrich Syndrome

WAS protein defect: defective signal transduction rom cell membranes to cytoskeleton in all lymphoid cells as well as platelet abnormalities

WASP?

34
Q

Wiskott Aldrich Syndrome

A

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

35
Q

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

A

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

36
Q

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

A

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

FMS Week 10 (4 decks)

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