B-cell Flashcards

Question

Describe XLA (X-linked Agammaglobulinemia)

Answer 1

**_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 •

Answer 2

_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

Answer 3

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

Answer 4

## Footnote _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)

Answer 5

## Footnote 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

Answer 6

## Footnote Diagnose: B-cell Flow Cytometry

Answer 7

"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

Answer 8

## Footnote _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

Answer 9

Most cases unknown etiology w/o family history * Age of onset, clinical course variable •Frequency (1:30k – 1:50K) – under diagnosed

Answer 10

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

Answer 11

## Footnote 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)

Answer 12

* Autoimmune disorders * Chronic lung disease * inflammatory bowel disorders * Granulomatous disease * Liver disease * Lymphoma * Cancers

Answer 13

## Footnote 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

Answer 14

## Footnote - 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

Answer 15

* Expressed on activated B- & T-cells * Defines "memory" B-cells Low numbers of switched memory B-cells is associated with: * granulomatous disease * lymphoproliferation * autoimmunity

Answer 16

Unswitched memory B-cells typically express: * CD27+ * IgD+ * Predominately produce IgM

Answer 17

Switched B-cells = * CD27+ * IgD- * Prodominately produce IgG, IgM, or IgA

Answer 18

1. TACI-Recetor 2. BAFF-Receptor 3. TWEAK

Answer 19

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

Answer 20

## Footnote 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

Answer 21

## Footnote 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

Answer 22

* 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

Answer 23

_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

Answer 24

_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

Answer 25

_Hyper-IgE syndromes (HIES / Jobs syndrome)_ * STAT-3 (AD) * DOCK8 (AR) * Tyk2 (AR)

Answer 26

_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

Answer 27

## Footnote 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

Answer 28

_Characteristic Features:_ * Coarse facial features * Prominent mandible * Hypertelorism * Broad nose * Skeletal abnormalities * Retained primary dentition * Scoliosis _Connective tissue disorders_ * Hyperextensitibility * Aortic aneurysms

Answer 29

_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

Answer 30

* High IgE \> 2000 but also high IgG & IgA * High Eosinophilia * **Low IgM** * High IgG & IgA * CD4 lymphopenia \> CD8 \> NK \> B cell

Answer 31

_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

Answer 32

Tyk-2 / HIES _Severe viral skin infections_ * HPV * HSV * VZV * Molluscum * Disseminated BCG * Vasculitis * Prone to lymphoma

Answer 33

**_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

Answer 34

**_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

Answer 35

## Footnote _**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

Answer 36

* 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

Answer 37

## Footnote * **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

Answer 38

## Footnote * 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**

Answer 39

## Footnote 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

Answer 40

## Footnote 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

Answer 41

## Footnote 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

Answer 42

## Footnote 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

Answer 43

* If an adult has a thymoma… * Usually older patients * Late onset immunodefic * Very little B-cells

Answer 44

_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

B-cell Flashcards

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