B Cell Dev

Describe B Cell Dev:

• Location?

• Initiation via?

• Describe what happens when Pro-B → Pre-B

B Cell Dev:

• Location:

  • mainly in bone marrow

• Initiation:

  • via direct interaction of stromal cells

    • VCAM-1 (stromal) - VLA-4 (pro-B-cell)

      • Both are adhesion molecules

      • other CAMs are also invovled

  • Once contact has been made → C-kit (Pro-B-Cells) - SCF (stem cell factor; stromal

• Pro-B → Pre-B

  • has IL-7 receptors

    • IL-7 is produced by stromal cells

      • req. for continued growth and maturation

  • Adhesion molecules on pre-B cells = down-regulated → pre-B cells detachment from stromal cells

Describe Stromal Cells

• What are they?

• Functions?

Describe Immunoglobulin genes

• What are they?

• Location?

• Importance?

Stromal cells

• What are they?

  • Nonlymphoid cells located in bone marrow

• Functions:

  • Provide microenvironments for B cell maturation

  • Interact w/ pro/pre-B cells

  • Secretion of several cytokines, including IL-7

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Immunoglobulin genes

• What are they?

  • multiple-gene segments in the germ-line

• Location:

  • Carried in the germ cells

• Importance:

  • Must be rearranged into functional genes

List and describe what happen in each B-cell developmental Stage

1. Pro-B cell

   • Early pro

     • Heavy-chain DH to JH gene rearrangement

   • Late Pro

     • VH to DH JH rearrangement

   • Upon completion of Heavy chain rearrangement → Pre-B Cell

   • NOTE:Earliest identifiable cell in the B-cell maturation process

2. Pre-B Cell

   • Expression of pre B-cell receptor

     • μ chain + Igα/β polypeptides (surrogate light chain molecule)

       • Surrogate light chains = not true immunoglobulin proteins

       • only found in primitive B cell precursors

   • μ chain + surrogate light chains reach cell surface →

     • signal transmission → halt heavy chain rearrangement

     • Begins Light-chain rearrangement

   • surrogate light chains ceases + pre-B cell receptor disappears from surface + μ chain trapped in ER

3. Immature B-cell

   • light-chain gene rearrangement

     • Kappa (κ), or Lambda (λ)

   • Ig gene rearrangements completed

     • Def: Light chain + heavy chains rearrangements completed → creates specificity

   • express IgM on the cell surface

4. Mature B-Cells

   • Coexpression of IgD and IgM

     • via production of 2 mRNAs ( one for μ + δ )

     • Low expression of IgD

       • levels increases when cells goes towards lymphoid organs

   • Negative Selection:

     • If fail → Dev. arrest + additional rearrangement → tests again (final test)

Describe these diseases associated w/ B cell dev

• Describe X-linked agammaglobulinemia

  • Pathophysiology

  • Consequences

  • Treatments

• Describe Burkitt’s lymphoma (FAB L3)

  • pathophysiolgoy

  • Consequences

X-linked agammaglobulinemia

• Pathophysiology:

  • B-cell development arrested @ pre B-cell stage → No circulating antibodies

    • b/c lack of essential signal transduction molecules

    • X-linked

• Consequences:

  • recurrent infections from extracellular bacteria

    • Haemophilus influenzae

    • Streptococcus pneumoniae

    • Streptococcus pyogenes

    • Staphylococcus aureus

• Treatment:

  • antibiotics and immunoglobulin from pooled blood

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Burkitt’s lymphoma (FAB L3)

• Pathophysiology:

  • MYC proto-oncogene (Chr8) + (translocation) immunogloblin heavy-chain gene (Chr14)

    • or to kappa light chain gene (Chr2)

    • or to lambda light chain gene (Chr22)

• Consequences:

  • many B cells tumors

Describe B1 cells

• Developmental Orgins:

• Compared to B2:

• Receptors:

• Antibodies:

• Lifespan:

• Chronic lymphocytic leukemia (CLL)

  • Source:

  • Initiating event

  • Risk Factors:

  • Testing

B1 cells:

• Developmental Orgins:

  • from stem cells during prenatal development

    • precedes dev. of B2 cells (normal B cells)

• Compared to B2:

  • Cell Surface: CD5, CD86, IgM, and IgD (variable existance)

  • Not part of adaptive immune system

  • No memory cells

  • Rearranged heavy chain genes = less diverse

    • thus → low affinity antibodies

    • polyspecificity

  • Antibodies:

    • against common bacterial polysaccharides

      • not against protein antigens

  • no evidence of somatic hypermutation

  • Capable of self-renewing

    • dependent on IL-10

• Receptors:

  • IgM + IgD receptors

    • more IgD then IgM

• Antibodies:

  • Secrete IgM and IgG3 antibodies

    • IgG3

      • small percentage of IgG antibodies

      • potent mediators of effector functions compared to other IgG subclasses:

        • ADCC

        • opsonization

        • complement activation

        • neutralization

• Lifespan:

  • eventually stop dev. in bone marrow

  • In adults: cell replications in peripheral circulation

• Chronic lymphocytic leukemia (CLL)

  • Source: B1 cells

  • Initiating event = unknown

  • Risk Factors:

    • Pesticides,

    • chemical fertilizers

    • Smoking

    • Heavy metals

    • Medical radiation

  • Testing: cannot withstand smear pressure → smudge cells

What happens when B cell Dev is complete

After B cell development is complete

• mature, naïve B cell leaves bone marrow → Recirculates between btw blood/secondary lymphoid tissues

  • secondary lymphoid tissues is where B cells encounter antigen

B Cell Activation

• Activation Steps

• Effects

• Describe ofmration of primary follicle

• B Cell Activation:

  • B cell encounters antigen → held in T cell areas → activated by CD4 T-Helper Cells → proliferate + dif. into plasma cells (in lymph nodes and spleen) → change in heavy-chain mRNA processing → synthesis of secreted form of Immunoglobulin

• Effects:

  • Antibody Secretion

  • Isotype Switching

  • Affinity Maturation

  • Memory B Cell formation

• Describe Primary Follicle Formation:

  • DC w/ antigen → migrate from Subcapsule to paracortical area (of LN) → interact w/ T cells (migrating through HEV) → B cells travels through HEV → pass through paracortex/primary follicle → interacts w/ T cells → both T/B proliferate to form primary focus

Describe Plasma Cells

• Function

• Properteis

Plasma Cells:

• function:

  • constitutive synthesis and secretion of antibody

    • protein synthesis cellular organelles = highly dev.

    • 10-20% of total protein is antibody

• Properties:

  • Terminally differentiated and cease to divide

  • Does not express cell-surface immunoglobulin or MHCII molecules

    • can’t respond to antigen/interact w/ T cells

  • Life span = 4 weeks

Describe Multiple Myeloma

• Pathophysiology

• clinical manifestations

• Multiple Myeloma and Calcium

Multiple Myeloma

• Pathophysiology:

  • Loss of control over B cell proliferation/antibody production

    • chromosomal translocation: heavy chain genes + oncogene → genomic instability → additional mutations and translocations

• Clinical Manifestations

  • Pain in the lower back, long bones or ribs

  • Generalized malaise

  • Infections

  • fever

  • Bleeding

  • Symptoms of hypercalcemia

    • Nausea

    • Fatigue

    • Thirst

  • Symptoms of hyperviscosity

    • Headaches

    • Bruising

    • Ischemic neurologic symptoms

  • Other neurologic symptoms

    • Peripheral neuropathy

    • Meningitis

• Multiple Myeloma and Calcium

  • RANKL

    • membrane protein belonging to TNF family

      • High Expression: lungs, thymus, lymph nodes

      • Low Expression: bone marrow, stomach, peripheral blood, spleen

    • Function: bone regeneration and remodeling control

  • Multiple Myeloma → overexpression of RANKL → act. osteoclasts → hypercalcemia