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ABAI > B-cell > Flashcards

B-cell Flashcards

1
Q

What two places (tissues) can B-cells develop from?

A
  • B-cells that develop from the fetal liver are called B-1 cells (less common)
  • Most B-cells develop in the BM, and are called B-2 cells
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2
Q

A
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3
Q

What do B-1 cell and B-2 cells become?

Which are most common, and what do they do?

A

B-1 cells (less common) develop in the fetal liver

  • Sub-class of B cells involved in humoral immune response
  • Not part of adaptive immune system, as they have no memory
  • B1 cells perform many of the same roles as other B cells: making antibodies against antigens (from infection or vaccination) and acting as antigen-presenting cells
  • B1 cells are commonly found in peripheral sites, but less commonly found in the blood

B-2 cells become one of two types:

  • Follicular B-cells (most) aka recirculating B-cells
  • Marginal zone B-cells

Follicular B-cells (most)

  • Express both IgD & IgM
  • Express CD21/CR2 receptors
  • Migrate from one secondary lymphoid organ to another looking for Ag

Marginal zone B-cells

  • Express only IgM (not IgD)
  • Express CD21/CR2 receptor
  • Have limited diversity of Ag receptors d/t only expressing IgM
  • Respond quickly to blood borne microbes
  • Tend to be found in the spleen and lymph nodes
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4
Q

Describe the make up of the B-cell receptor

A

Membrane IgM & IgD have two molecules Igα & IgB that make up the BCR complex

  • The Igα & IgB chains work similarly to the CD3 and zeta proteins in the TCR

Also have co-stimulatory proteins

  • CR2 (complement receptor 2) – aka CD21
  • CD19 (expressed in all B lineage cells) - forms complex w/ CR2 (CD21)
  • CD81
  • CD19 recruits cytoplasmic signaling proteins to the membrane and it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways
  • Have ITAMs that associate with Src kinases such as Lyn, Fyn, and Blk

CD81 interacts with T-cells (CD4 and CD8) and provides a costimulatory signal with CD3

Also have inhibitory B-cell coreceptors:

  • CD22
  • FcγRIIB
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5
Q

What is a mitogen?

A
  • A mitogen is a peptide or small protein that induces a cell to begin cell division: mitosis.
  • Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen.
  • The mechanism of action of a mitogen is that it triggers signal transduction pathways involving mitogen-activated protein kinase (MAPK), leading to mitosis.
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6
Q

What mitogens stimulate T-cells?

A
  • Pokeweed
  • Phytohemagglutin

Concanavalin A

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7
Q

What mitogens stimulate B-cells?

A
  • Pokeweed (PWM)
  • LPS

SAC (Staph Aureus Cowan)

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8
Q

What is a conjugated vs unconjugated vaccine?

A

  • Conjugate vaccines generate long term memory cells allowing rapid boosting of immunity with booster doses up to many years later
  • A conjugate vaccine is a type of vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen.
  • The antigen of some pathogenic bacteria does not elicit a strong response from the immune system, so a vaccination against this weak antigen would not protect the person later in life
  • Most commonly, the weak antigen is a polysaccharide that is attached to strong protein antigen
  • In the polysaccharide vaccine, only the sugar part of the bacteria, the capsule, is included as the antigen to stimulate the immune response
  • In the conjugated vaccine, it’s actually the sugar joined to the carrier protein
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9
Q

What are the protein based vaccines vs carbohydrate based vaccines?

A

Protein based vaccines

  • Diphtheria
  • Pertussis (acellular)
  • Tetanus
  • Hep B

Carbohydrate based vaccines (pretty much everything else)

  • Sugar from the bacteria capsule
  • Either by itself (unconjugated polysaccharide)
  • Or with a carrier protein (conjugated polysaccharide)
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10
Q

What are the conjugated polysaccharide and unconjugated polysaccharide vaccines?

A

Conjugated polysaccharide vaccines

•Hib

Prevnar

Unconjugated polysaccharide vaccines

  • Neisseria meningitides
  • Pneumovax
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11
Q

What are the vaccines that can be used to check both T & B-cell function, as well as the vaccines that only evaluate B-cell function?

A

T-cell independent vaccines

  • Conjugated polysaccharide vaccines
  • Hib
  • Prevnar
  • Ags linked to a carrier protein

Unconjugated polysaccharide vaccines

  • Neisseria meningitides
  • Pneumovax
  • Only 2 years of age and older can generate a response to these vaccines

B-cell fxn only

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12
Q

What vaccines are T-cell dependent?

What type of antigen do they use?

A

T-cell dependent vaccines

  • Protein based vaccines
  • Diphtheria
  • Pertussis (acellular)
  • Tetanus
  • Hep B

Use MHC class I & II molecules

T-cell dependent or independent

  • Nucleic acid based vaccines
  • In clinical trials
  • Involve MHC I & II, TLR 9 (CpG recognition on DCs)
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13
Q

What vaccines are T-cell independent?

What type of antigen do they use?

A

T-cell independent vaccines

  • Protein based vaccines
  • Diphtheria
  • Pertussis (acellular)
  • Tetanus
  • Hep B
  • Use MHC class I & II molecules

T-cell dependent or independent

  • Nucleic acid based vaccines
  • In clinical trials
  • Involve MHC I & II, TLR 9 (CpG recognition on DCs)
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14
Q

When should you consider a B-cell (antibody) deficiency as a cause of a condition?

A
  • Recurrent sinopulmonary infections
  • Enteroviral infections (espec in XLA)
  • Giardiasis
  • Autoimmune phenomenon
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15
Q

Name the major stages of B-cell development (6)

A
  1. Stem cell
  • (Bone Marrow)
  • (CD43+)
  1. Pro-B cell
  • (Bone Marrow)
  • (CD43+)
  • Heavy chain combines D & J segments
  1. (Large) Pre-B cell
  • (Bone Marrow)
  • (CD43+)
  • Heavy chain combines V to DJ segments
  1. (Small) Pre-B cell
  • (Bone Marrow)
  • (CD43+)
  • Heavy chain gene fxnl (VDJ)
  • Variable chain combines V to J segments
  1. Immature B cell
  • (Bone Marrow)
  • (IgM / CD43-)
  • Membrane IgM(u )& light chain (k or l) present
  1. Mature B cell
  • First time B-cell outside the BM (periphery)
  • (IgM & IgD / CD43-)
  • Alternative splicing of VDJ – Constant, allow membrane u & δ to be present
  • B-cell Activation / Prolif / Differentiation
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16
Q

What are the important B-cell surface markers to identify?

A

CD 19

  • CD19 is expressed on:
  • Pre-B1
  • Pre-B2
  • Immature B-cells
  • Mature B cells
  • Its expression in plasma cells is downregulated

CD20

  • CD20 is expressed on:
  • Pre-B2
  • Immature B-cells
  • Mature B cells
  • Its expression in plasma cells is abolished
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17
Q

List the major conditions associated with B-cell deficiencies

A
  1. Agammaglobulinemia – block in development from Pro-B to Pre-B cell
    1. X-linked (Brutons tyrosine kinase / BTK / aka XLA) – by far most common cause (85%)
    2. Autosomal Dominant (E47 – aka E2A or TCF3)
    3. Autosomal Recessive = most common form of AR A-gammaglob is u-heavy chain defect
      1. u-heavy chain defect still only 5% of total cases
  2. Common Variable Immunodeficiency (most cases are not inherited)
    1. CD27 receptor defect = low number of switched B-cells (low level of memory B-cells)
    2. CD21 (aka CR2) receptor defect = is the C3d complement receptor
    3. TACI receptor mutation (10% of CVID cases) – receptor for BAFF & APRIL (isotype switching)
    4. BAFF receptor mutations – important for B-cell survival / isotype switching
    5. TWEAK
  3. CVID-like disorders
    1. ICOS – binds B7-like ligands on B-cells (ICOS-L & others)
      1. Panhypogammaglobulinemia, impaired spec. Ab response, severe reduction in switched memory B-cells (normal T-cell fxn)
      2. ICOS will be on the boards
    2. Hyper-IgM Syndrome
      1. Mutation in CD40, CD40L, NEMO (NF-KB issue)
      2. AR mutation in AID (Activation induced Cytidine Deaminase) or UNG
    3. Mutations in CD-19 complex (CD19 / CD21 (aka CR2) / CD81
      1. All are Auto-recessive
      2. CD81 deficiency leads to absence of CD19 expression
    4. CD20 defect
      1. AR – low IgG, normal IgA, IgM, mild phenotype
    5. Lysine specific methyl-transferase 2D (KMT2D)
      1. AD – cause 75% of Kubuki Syndrome
  4. Hyper-IgE Syndromes (HIES)
    1. STAT-3 (AD)
    2. DOCK8 (AR)
    3. Tyk2 (AR)
  5. IgA deficiency
  6. Specific Antibody Deficiency
    1. Normal IgG/IgA/IgM, normal T-cell fx, abnormal response to vaccines (espec Polysaccharide Ag’s)
  7. Transient Hypogam of Infancy (THI) – nadir IgG 3-6 months (400mg/dL)
    1. >2SD below normal IgG for that age (w or w/o other isotypes affected)
    2. Persists past 6 months of age (nearly all normalize by the age of 5 years)
  8. Good Syndrome – adult onset hypogammaglobulinemia w/ thymoma
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18
Q

Describe Transient hyogammaglobulinemia of infancy

A

THI is defined as:

  • Low IgG in infants over 6 months of age
  • IgG is significantly lower than 97% of infants at the same age
  • Less than 2 standard deviations
  • Typically the IgG level is under 400 mg/dl
  • IgA and IgM antibodies may also be lower
  • However, these infants typically make normal or near normal antibodies
  • May present with sinopulmonary or GI infections, thrush or meningitis
  • Though usually not severe
  • May even be completely infection free
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19
Q

When is a baby’s IgG typically at it’s lowest point?

A
  • At birth, IgG = mother’s IgG
  • Nadir = 3-6 months (~ 400 mg/dL)
  • More pronounced in premature infants
  • IgG = 60% of adult levels by age 1
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20
Q

Describe Selective IgA Deficiency

A

Most common immunodeficiency

SIgAD is defined as:

  • Low IgA < 7 mg/dL
  • Age must be over 4 years old
  • Some kids need up to age 7 for IgA to normalize
  • IgM and IgG normal
  • Normal T-cell fxn
  • Poor polysaccharide response despite pneumovax
  • Most individuals asymptomatic
  • Can correlate w/ atopy and autoimmune dz
  • Frequently caused by anti-seizure meds
  • Can be associated w/ CVID à TACI mutation
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21
Q

What are the common causes of hypogammaglobulinemia (IgG)

A

Hypogammaglobulinemia can be caused by either a primary or secondary immunodeficiency

PID usually have a delay of several years b/w initial clinical presentation and diagnosis.

Hypogammaglobulinemia most frequently develops as a result of secondary or acquired immune deficiencies

These include:

1) Blood cancers

  • Chronic lymphocytic leukemia (CLL)
  • Lymphoma
  • Myeloma

​2) HIV

3) Nephrotic syndrome
4) Poor nutrition
5) Protein-losing enteropathy
6) Receiving an organ transplant
7) Radiation therapy.

The most common cause of an isolated IgG is:

  • Steroids (COPD/Asthma/joint issues)
  • Also think of protein enteropathy
  • Rituximab / Chemotherapy
  • Anti-seizure med
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22
Q

What type of infections might you see in a selective IgA deficiency?

What can cause a selective IgA deficiency?

A

Typically is asymptomatic…but may see:

  • Sinopulmonary infections
  • Giardia

•Check antibody responses in those w/ recurrent infections

Look for secondary cause:

  • Phenytoin, carbamazepine, valproic acid
  • Sulfasalazin
  • Ecaptopril
  • Thyroxin
  • Can be part of AT, IgG2 subclass defic, CMC
  • Rarely treatment necessary (Tx = IVIG)
  • Monitor for CVID progression
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23
Q

What is Agammaglobulinemia?

A

Agammaglobulinemia:

  • Inability to move past the Pro-B-cell stage
  • Pre-B-cell receptor checkpoint defect
  • Causes an inability to make NF-kB
  • if b-cells can’t activate NF-kB, they can’t develop
  • NF-kB leads to differentiation of B-cells

All B-cells will be low / absent

•Ig G, IgM, IgA, IgE

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24
Q

What are the most common causes of Agammaglobulinemia?

A

3 main types:

1) X-linked
* BTK (Brutons Tyrosine Kinase)
2) AD
* E47 (aka EA2 or TCF3)
2) AR

  • IgM heavy chain (m heavy chain) à most common AR
  • Surrogate light chain (l5)
  • Igα
  • Igβ
  • BLNK
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25
Q

Describe XLA (X-linked Agammaglobulinemia)

A

XLA (aka Brutons):

  • Btk mutation (Brutons Tyrosine Kinase)
  • 85% of all agammaglobulinemia cases
  • Maturational arrest at the Pre-B lymphocyte
  • Pre-B-cell receptor checkpoint defect
  • Btk phosphorylates PLCy2→PLCy2 activates NF-kB →needed for B-cell development and differentiation
  • Infections usually start when mother’s immunity stops (2-3 months)

All B-cells will be low / absent (<1%)

  • Ig G, IgM, IgA, IgE
  • IgG < 200
  • T-cell function is normal

•

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26
Q

What are the clinical findings in XLA?

  • What will the lymph nodes look?
  • What type of infections are expected?
  • Treatment?
A

Clinical Findings

  • Small / absent lymphoid tissue
  • No germinal centers

Typical infections w/ XLA:

  • Sinopulmonary infections
  • Atypical bacteria
  • GI infections
  • Enteroviral encephalitis
  • ECHO virus CNS infection
  • Ecthyma or pyoderma gangrenosum – H. pylori
  • Septic arthritis / Osteo
  • Lymphoreticular and colorectal malignancies
  • Tx = IVIG and Abx à avoid live immunizations
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27
Q

How would you diagnose XLA?

A

Diagnose:

B-cell Flow Cytometry for Btk à (normal on the left)

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28
Q

Describe AR Agammaglobulinemia

A

AR Agammaglobulinemia

•IgM heavy chain (u heavy chain)

  • Most common AR ⇒ BOARD Question
  • Surrogate light chain (l5)
  • Igα
  • Igβ
  • BLNK
  • Maturational arrest at the Pre-B lymphocyte
  • Pre-B-cell receptor checkpoint defect, BCR, or downstream

All B-cells will be low / absent (<1%)

  • Ig G, IgM, IgA, IgE
  • IgG < 200
  • T-cell function is normal
  • Infections usually start when mother’s immunity stops (2-3 months)
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29
Q

Name the most common causes of autosomal recessive Agammaglobulinemia (4)

Which is THE most frequent cause?

A

1) Ig M heavy chain (most common AR)
* No surface expression of IgM
2) Surrogate light chain (l5)
* Necessary for signal transduction of pre-BCR
3) Igα & Igβ
* Associated w/ and necessay for BCR signaling à ITAM motif
4) BLNK
* Adaptor protein needed for downstream signaling of BCR

30
Q

How would you diagnose AR Agammaglobulinemia?

A

Diagnose:

B-cell Flow Cytometry

31
Q

What are the diagnostic criteria for CVID?

A

“TRUE CVID” Criteria

Decrease in 2 / 3 major isotypes (including IgG)

  • > 2 SD below the mean
  • Onset over 2 years of age
  • Absent isohemagglutinins and poor response to vaccines (protein and PS antigens)
  • Defined causes of hypogam must be excluded
32
Q

By academic standards, what are 3 common mistakes in diagnosing CVID by the community allergist

A

True CVID patients:

  1. Can not have normal IgG, IgM, IgA with abnormal antibody response to vaccines
  2. Do not have low IgG levels as a secondary result of medications (steroids in COPD / asthma, Rituximab in rheumatology pts)
  3. Is not diagnosed d/t a low IgG subclass

FYI = More common to have low IgA than IgM

33
Q

Is CVID typically inherited?

What is the frequency of CVID in the general population?

A

Most cases unknown etiology w/o family history

  • Age of onset, clinical course variable

•Frequency (1:30k – 1:50K) – under diagnosed

34
Q

What immunodeficiency can be associated in family members of someone who has CVID?

A

•Family history of IgA deficiency in 8-10% of cases

35
Q

Do CVID patients get opportunistic infections?

What do they typically die from?

A

Most CVID patients don’t get opportunistic infections

Typically die from non-infectious risk factors

  • GI disease
  • Liver disease/hepatitis
  • Lymphoma
  • Chronic lung disease (bronchiectasis related)
36
Q

What type of non-infectious complications (cxns) are often associated with those who have CVID?

A
  • Autoimmune disorders
  • Chronic lung disease
  • inflammatory bowel disorders
  • Granulomatous disease
  • Liver disease
  • Lymphoma
  • Cancers
37
Q

Most common lung disorder in CVID

A
38
Q

What is GLILD?

A

Granulomatous & Lymphocytic Interstitial Lung Disease

Granulomatous–lymphocytic interstitial lung disease (GLILD) is a lung complication of CVID

  • It is seen in approximately 15% of patients with CVID
  • Histologically defined as the presence of (non-caseating) granuloma and lymphoproliferation in the lung
  • GLILD is often associated with other auto-immune features such as:
  • splenomegaly
  • adenopathy
  • cytopenias
  • Can also be defined as abnormalities on lung imaging (CT scan) together with evidence of granulomatous inflammation elsewhere

Although infections and complications of infection such as bronchiectasis are more common complications of CVID in the lung, the presence of immune manifestations including GLILD is important because this has been associated with greater risk of death

39
Q
A
40
Q

What are memory B-cells?

What is an important cell surface marker for memory B-cells?

A

  • B lymphocytes that memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response
  • Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response
  • Memory B cells are typically distinguished by the cell surface marker CD27
  • Memory B cells that lack CD27 are generally associated with exhausted B cells or certain autoimmune conditions such as HIV, lupus, or rheumatoid arthritis
  • The receptor CCR6 is generally a marker of B cells that will eventually differentiate into Memory B-cells
  • CCR6 rec’s allow them to move out of the germinal center and into the tissues where they have a higher probability of encountering antigen
41
Q

What is significant about CD27?

A
  • Expressed on activated B- & T-cells
  • Defines “memory” B-cells

Low numbers of switched memory B-cells is associated with:

  • granulomatous disease
  • lymphoproliferation
  • autoimmunity
42
Q

What would the cell surface markers look like for unswitched B-cells for the following items?

CD27 (+/-) ?

IgD (+/-) ?

What would they prodominately produce (IgD/ IgG / IgA / IgM / IgE)?

A

Unswitched memory B-cells typically express:

  • CD27+
  • IgD+
  • Predominately produce IgM
43
Q

What would the cell surface markers look like for switched B-cells for the following items?

  • CD27 (+/-) ?
  • IgD (+/-) ?
  • What would they prodominately produce (IgD/ IgG / IgA / IgM / IgE)?
A

Switched B-cells =

  • CD27+
  • IgD-
  • Prodominately produce IgG, IgM, or IgA
44
Q

Name the TNF family of mutations that can contribute to the development of CVID

A
  1. TACI-Recetor
  2. BAFF-Receptor
  3. TWEAK
45
Q

What is TACI?

A

Transmembrane Activator & Calcium Modulator

  • TNF-Rec family
  • Expressed on B-cells
  • TACI’s ligands are BAFF & APRIL
  • Responsible for 8-10% of CVID cases

TACI is important in:

  • B-cell isotype switching
  • T-cell independent responses

**If you have a TACI mutation with CVID, you’ll have more severe disease

  • increased incidence of autoimmunity, splenomegaly, lymphadenopathy
46
Q

How does TACI mutation cause CVID?

A

BAFF and APRIL proteins signal through the TACI receptor to activate several transcription factors including NFAT, AP-1, and NF-kappa-B

TACI mutations (chromosome 17) are typically heterogenious (majority of cases)

  • TACI mutations cause phenotypes similar to CVID, but not all individuals will develop CVID (is a risk factor, but not an absolute) – about 9% of total CVID cases
  • Siblings w/ identicle TACI mutation may not develop CVID
  • Often a delayed onset of symptoms (late childhood or adulthood)
  • increased incidence of autoimmunity, splenomegaly, lymphadenopathy

Those with homozygous mutations all CVID, but don’t have autoimmunity

Activation of NFAT and AP-1 is required for transcription of: IL-2, GM-CSF, IL-3, and IFN-γ. In the thymus, FasL expression, which allows for potential cell death, also requires cooperation between NFAT and AP-1

47
Q

What is BAFF?

A

B-cell Activating Factor / BAFF-receptor

  • BAFF is a cytokine from the TNF family that binds to the BAFF-Receptor
  • Also known as B Lymphocyte Stimulator (BLyS)
  • Predominately found on B-cells
  • It’s activating ligand is BAFF
  • Important in isotype switching and plasma cell survival
  • Interaction between BAFF and BAFF-R activates classical and noncanonical NF-κB signaling pathways
  • This interaction triggers signals essential for the formation and maintenance of B cell, thus it is important for a B-cell survival
48
Q

What is the BAFF-R mutation presentation for CVID?

Immunoglobulin findings:

  • IgG ?
  • IgM ?
  • IgA ?

Vaccine response:

  • Response to protein Ag’s ?
  • Response to PS Ag’s ?
A
  • Autosomal recessive
  • Often presents in families
  • Can have variable penetrance, siblings with same mutation may be normal / not have CVID
  • Late onset pneumonias

Immunoglobulin findings:

  • Variable low IgG
  • low IgM
  • high IgA

Vaccine response:

  • Normal Ab response to protein Ag’s
  • Decreased to PS Ag’s
49
Q

What is TWEAK?

Immunoglobulin findings:

IgG ?

IgM ?

IgA ?

Vaccine response:

Response to protein Ag’s ?

Response to PS Ag’s ?

A

TNF-related weak inducer of apoptosis

  • The TWEAK leads to signaling cascades for the NF-κB pathways and the MAPK pathway

TWEAK mutation:

  • Autodominant mutation
  • A mutant form of TWEAK binds to BAFF-R, causing an inhibition of NF-kB signaling in B-cells
  • Recurrent sinopulmonary infections

Immunoglobulin findings:

Variable low IgG

low IgM

low IgA

**INCREASED double neg T-cells

Vaccine response:

Decreased Ab response to protein Ag’s

Decreased to PS Ag’s

50
Q

What is ICOS?

How would it contribute to immunodeficiency?

What would the B-cell and T-cell findings look like in an ICOS mutation?

A

ICOS - Inducible (T-cell) costimulator

  • Checkpoint protein encoded by the ICOS gene
  • CD278 / ICOS (Inducible T-cell Co-Stimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated T cells
  • It is thought to be important for Th2 cells in particular

ICOS binds B7-like ligands on B-cells

  • ICOS-L

ICOS mutations cause:

  • Pan-hypogammaglobulinemia
  • Reduced B-cell numbers
  • Severe reduction in switched memory B-cells
  • Normal T-cell function
  • Impaired specific Ab production

Will present with a CVID-like picture

Can be detected with Flow Cytometry

****ICOS will be on the boards

51
Q

List the causes of Hyper IgE Syndromes (HIES)?

A

Hyper-IgE syndromes (HIES / Jobs syndrome)

  • STAT-3 (AD)
  • DOCK8 (AR)
  • Tyk2 (AR)
52
Q

Describe the classic triad of HIES:

What you expect to find with regard to:

  • IgE level
  • Eosinophils
  • Ig G / Ig M / IgA levels
  • Th17 levels
A

High IgE with the Triad of:

  • Recurrent skin infections
  • Recurrent lung infections
  • Severe eczema

High IgE

Additional findings:

  • IgE > 2000
  • Eosinophilia
  • Normal IgM
  • Th17 levels decreased
53
Q

What does a STAT3 mutation cause?

What type of infections would you expect to find?

A

Signal transducer and activator of transcription 3 (STAT3)

  • AD loss of function mutation
  • Hyper IgE Syndrome
  • Recurrent infections
  • Abscesses
  • Mucocutaneous candidiasis
  • Pneumonia with pneumatoceles

•

  • Severe eczema
  • Eosinophilic pustular folliculitis

Bacterial infection profile

  • Staph / Strep pneum / HIB / Candida
  • Secondary infections by Pseudomonas & Aspergillous
54
Q

What are the physical exam / characteristic physical features often found with HIES (STAT-3)

A

Characteristic Features:

  • Coarse facial features
  • Prominent mandible
  • Hypertelorism
  • Broad nose
  • Skeletal abnormalities
  • Retained primary dentition
  • Scoliosis

Connective tissue disorders

  • Hyperextensitibility
  • Aortic aneurysms
55
Q

What does a DOCK8 mutation cause?

What type of infections would you expect to find?

A

DOCK8 / HIES

  • Autosomal Recessive
  • Severe viral skin infections
  • HPV
  • HSV
  • VZV
  • Molluscum

•

  • Mucocutaneous candidiasis
  • Pneumonias, but no pnematoceles
  • Eczema & allergies

Risk of malignancies

  • squamous cell and lymphoma
56
Q

What you expect to find with regard to in DOCK8 mutation (HIES):

IgE level

Eosinophils

Ig G / Ig M / IgA levels

T-cell levels

A
  • High IgE > 2000 but also high IgG & IgA
  • High Eosinophilia
  • Low IgM
  • High IgG & IgA
  • CD4 lymphopenia > CD8 > NK > B cell
57
Q

What occurs in a Tyk-2 mutation?

A

Tyk-2 (HIES)

  • AR
  • Similar to DOCK-8
  • Tyk-2 involved in IL-12 signaling pathway to produce IL-12
  • Tyk-2 is part of the JAK family kinases (JAK 1,2,3 & Tyk-2)

IL-12 has two subunits

  • p40
  • p35

►

  • The IL-12 receptor (IL-12R) also has 2 subunits
  • IL-12Rβ1 à binds the p40 subunit
  • IL-12Rβ2 à binds the p35 subunit
  • IL-12Rβ1 binds p40 subunit ► Tyk2 activated STAT4 ► increased IL-12 and IFN-y production
  • IL-12Rβ2 à binds the p35 subunit à Tyk2 and Jak2 à STAT4 à increased IL-12 and IFN-y production
58
Q

What types of infections / complications would you expect to find with Tyk-2 mutation?

A

Tyk-2 / HIES

Severe viral skin infections

  • HPV
  • HSV
  • VZV
  • Molluscum
  • Disseminated BCG
  • Vasculitis
  • Prone to lymphoma
59
Q

List the types of Hyper IgM Syndromes

A

Most common feature:

  • Normal or high IgM
  • Low IgA, IgG, IgE

5 types

1) X-LINKED Hyper IgM Syndrome (most common)
* CD40L (CD154) mutation
2) Hyper IgM Syndrome Type 2
* Activation-induced cytidine deaminase (AID) deficiency
3) Hyper IgM Syndrome Type 3
* AR mutation of CD40 gene à no CD40 on B-cell
4) Hyper IgM Syndrome Type 4
* Cause is unknown
5) Hyper IgM Syndrome Type 5
* Muation in the UNG gene needed for somatic hypermutation

60
Q

Describe Type I HIGM Syndrome

A

X-LINKED mutation of CD40L (CD154) mutation (TNFS5)

  • CD40L is missing on the T-cells

CD40L-CD40 binding interaction is required for:

  • Class switching
  • Production of memory B-cells
  • Germinal center development

CD40L is only on the T-cell, and appears after the T-cell has been activated by an APC

Most common feature =

  • Normal or high IgM
  • Low IgA, IgG, IgE
  • CD40L type has Neutropenia
  • Absent germinal centers
  • Opportunistic infections, as CD40-CD40L facilitates T-cell response to intracellular pathogens
61
Q

Describe Hyper IgM Syndrome Type 2

A

AR mutation in AICDA gene

  • Causing a deficiency in the Activation-induced cytidine deaminase (AID) protein
  • AID is involved in antibody diversification by of immunoglobulin (Ig) diversification:
  • Somatic hypermutation = antibody genes are minimally mutated to generate a library of antibody variants, some of which with higher affinity for a particular antigen than any of its close variants
  • Class switch recombination

Most common HIGM Syndrome features =

•Normal or high IgM

•Low IgA, IgG, IgE

  • CD40L type has Neutropenia
  • Absent germinal centers

**Type II HIGM (AID deficiency) does not develop opportunistic infections like Type I & 3

62
Q

What does activation-induced cytidine deaminase (AID) do?

A
  • Activation-induced cytidine deaminase (AID) function under physiological and inflammatory conditions.
  • AID is expressed only in activated B cells and is a key molecule for generating immune diversity by inducing:
  • Somatic hypermutation (SHM)
  • Class-switch recombination (CSR) in immunoglobulin genes
63
Q

Describe Type 3 Hyper IgM Syndrome

A

  • Auto-recessive mutation of CD40 gene
  • CD40 is absent on the B-cells

CD40L-CD40 binding interaction is required for:

  • Class switching
  • Production of memory B-cells
  • Germinal center development

CD40L is only on the T-cell, and appears after the T-cell has been activated by an APC

Most common features =

  • Normal or high IgM
  • Low IgA, IgG, IgE
  • Absent germinal centers
  • Opportunistic infections, as CD40-CD40L facilitates T-cell response to intracellular pathogens
64
Q

Describe Type 5 Hyper IgM Syndrome

A

  • AR mutation in UNG protein
  • Very similar to Type 2 (AID defic)

Most common HIGM Syndrome features =

•Normal or high IgM

•Low IgA, IgG, IgE

Similar to type 2 HIGM:

  • susceptibility to bacterial infections
  • lymphoid hyperplasia
  • lack of opportunistic infections
65
Q
A
66
Q
  • AID deaminates cytosine into uracil in targeted DNA (e.g., in immunoglobulin switch or variable regions) followed by uracil removal by UNG
  • Mutations in the UNG gene are associated with a profound impairment in CSR and with a biased pattern of SHM
A
67
Q

What is CD19?

A

CD19 molecule (Cluster of Differentiation 19) is expressed on all B lineage cells

CD19 is essential for B cell differentiative events including the formation of B-1, germinal center, and marginal zone (MZ) B cells

CD19 plays two major roles: ​

  • acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane
  • works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways

CD19 interacts with:

CD81

CD21

Complement receptor 2

68
Q

What can mutations in the CD19 complex lead to?

A

CD19 complex mutations can lead to CVID

CD19 complex

  • CD19
  • CD81
  • CD21

There can be a mutation in any (CD19, CD81, or CD21)

  • All are AR
  • CD21 mutation causes more mild phenotype
  • CD19 & CD81 more severe
  • All can be detected by Flow Cytometry
69
Q

A mutation in CD81 can lead to what?

A

Causes an absence in CD19 expression

  • Leads to CVID
  • Causes a severe phenotype

CD19 is essential for B cell differentiative events including:

  • the formation of B-1 germinal center and marginal zone (MZ) B cell
70
Q

What does a CD20 mutation cause?

What does a Lysine specific methyl-transferase 2D (KMT2D) mutation cause?

A

CD20 defect

  • Auto-Recessive
  • low IgG, normal IgA, IgM
  • mild phenotype

Lysine specific methyl-transferase 2D (KMT2D)

  • Auto-Dominant
  • causes 75% of Kubuki Syndrome
  • Similar to CVID
  • Causes high incidence of autoimmunity & GLILD
71
Q

What is Good Syndrome?

A
  • If an adult has a thymoma…
  • Usually older patients
  • Late onset immunodefic
  • Very little B-cells
72
Q

In the following disorders, what are the typical lab findings:

  • B-cell numbers
  • IgG level
  • IgA level
  • IgM level
  • Response to immunization

  1. IgA deficiency
  2. XLA
  3. CVID
  4. Hyper IgM
  5. Specific Ab defic
  6. Steroid induced
A

IgA

  • B-cell numbers = normal
  • IgG level = normal
  • IgA level = absent (< 7)
  • IgM level = normal
  • Response to immunization = normal

XLA

  • B-cell numbers = absent
  • IgG level = absent
  • IgA level = absent
  • IgM level = absent
  • Response to immunization = absent

CVID

  • B-cell numbers = NL > low
  • IgG level = low
  • IgA level = usually low
  • IgM level = usually low
  • Response to immunization = low

Hyper IgM

  • B-cell numbers = normal
  • IgG level = low
  • IgA level = usually low
  • IgM level = normal / high
  • Response to immunization = low

Specific Ab Defic

  • B-cell numbers = normal
  • IgG level = normal
  • IgA level = normal
  • IgM level = normal
  • Response to immunization = low

Steroid induced

  • B-cell numbers = NL>low
  • IgG level = low
  • IgA level = NL / slightly reduced
  • IgM level = NL / slightly reduced
  • Response to immunization = NL / slightly reduced

ABAI (7 decks)

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