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THE DEVELOPMENT OF B-LYMPHOCYTES. STAGES IN LIFE CYCLE OF B-LYMPHOCYTES *Stage 1 *Maturation in bone marrow with development of functional receptors *Stage.

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Presentation on theme: "THE DEVELOPMENT OF B-LYMPHOCYTES. STAGES IN LIFE CYCLE OF B-LYMPHOCYTES *Stage 1 *Maturation in bone marrow with development of functional receptors *Stage."— Presentation transcript:

1 THE DEVELOPMENT OF B-LYMPHOCYTES

2 STAGES IN LIFE CYCLE OF B-LYMPHOCYTES *Stage 1 *Maturation in bone marrow with development of functional receptors *Stage 2 *Testing for and elimination of self-reactive receptors *Stage 3 *Mature naïve cells move to secondary lymphoid tissues *Stage 4 *Antigen contact with differentiation into plasma cells and memory cells

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6 B-CELL DEVELOPMENT IN BONE MARROW *Stages are defined by rearrangement and expression of IG genes *Early Pro-B cells *Earliest cells in B-cell lineage *Rearrangement of variable domain of heavy chains *D to J *Late Pro-B cell *Rearrangement of variable domain of heavy chains *V to DJ

7 B-CELL DEVELOPMENT IN BONE MARROW *Large Pre-B cell *M expressed on cell surface along with surrogate light chains and signal transduction molecules *Pre-B cell receptor *Small Pre-B cell *Pre-B cell receptor not present *Most M chains inside cell *Light chain rearrangement begins

8 B-CELL DEVELOPMENT IN BONE MARROW *Immature B-cell *Heavy and light chains assembled and transported to surface as IgM receptor complex *Randomness of gene rearrangements leads to self- reactive B-cells *Mature B-cell *IgD expressed on cell surface *Called naïve B-cells

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10 Figure 4-4

11 B-CELL DEVELOPMENT IN BONE MARROW *Development depends on non-lymphoid stromal cells *Function of stromal cells *Specific contact through cell adhesion molecules (CAM’s) *VCAM-1 to VLA-4 on early pro-B cells *Produce growth factors for bound B-cells *Stem cell factor (SCF) *Interleukin-7 (IL-7) *Growth factors *Stem cell factor stimulates (G/P) of Early pro-B cells *Interleukin-7 stimulates (G/P) of Late pro-B and L/S pre-B cells

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13 GENE REARRANGEMENTS AND B- CELL SURVIVAL *Gene rearrangement process is imprecise and classified as *Unproductive *Not translated into IG chain *B-cell dies *Productive *Translated into IG chain *Development proceeds *Immunoglobulin loci *Each B-cell has 2 copies on homologous chromosomes *Rearrangements made on both

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16 PROTEINS INVOLVED IN REARRANGEMENT AND EXPRESSION OF IG GENES *Several categories of specialized proteins are required *Lymphoid specific recombination *RAG-1 and RAG-2 *N-nucleotide addition *TdT *Surrogate light chains *Lambda5 and VpreB *Signal transduction *IG-alpha, IG-beta, CD45 and Btk *Transcription factors *EBF and Oct-2

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19 SIGNAL TRANSDUCTION AND BRUTON’S TYROSINE KINASE (BTK) *Bruton’s tyrosine kinase (Btk) *Encoded by gene on X chromosome *Essential for B cell maturation *Mutation in gene *B cells maturation stops at pre-B cell stage *Results in immunodeficiency called *Bruton’s X-linked agammaglobulinemia *Immunodeficiency results in recurrent sinopulmonary infections with *Streptococcus pneumoniae *Haemophilus influenzae

20 POPULATIONS (SUBSETS) OF B CELLS *B-1 cells (minor subset) *Develop early in embryonic life with unknown origin *Express CD5 (CD5 B cells) *Self-renewing *Primary location is body cavities (pleural / peritoneal) *Produce polyspecific antibodies *B-2 cells (major subset) *Develop after birth *Do not express CD5 glycoprotein *Replaced from bone marrow *Primary location is lymphoid organs *Produce highly specific antibodies

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22 NEGATIVE SELECTION AND FURTHER DEVELOPMENT OF B CELLS *Self reactive immature B cells are either *Eliminated or inactivated *IgM receptor may react with *Cell surface or soluble self antigens *Reactions with cell surface antigens *Induced to commit suicide by apotosis *Clonal deletion *Reactions with soluble antigens *Rendered unresponsive (anergic) to antigen *Maturation continues with reduced surface IgM

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24 SELECTION AND FURTHER DEVELOPMENT OF B CELLS *B cells leave bone marrow and circulate between blood and secondary lymphoid tissues *Secondary lymphoid tissue contains primary lymphoid follicles *Primary lymphoid follicle *Area where B cells congregate in association with specialized stromal cells (follicular dendritic cells) *Passage through primary lymphoid follicle and contact with follicular dendritic cells (FDC) necessary for survival *Few days with no passage *3 to 8 weeks with passage

25 CIRCULATION OF B CELLS THROUGH SECONDARY LYMPHOID TISSUES (LYMPH NODES) *Chemokines attract B cells to leave blood and enter cortex of lymph node via high endothelial venule (HEV) *Chemokines attract B cells to lymph node and primary lymphoid follicle *No encounter with antigen *B cells leave node via efferent lymphatic vessel *Anergic B cells detained in T cell area *Induced to commit suicide by apoptosis

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28 B CELL ENCOUNTER WITH ANTIGEN IN SECONDARY LYMPHOID TISSUES *Encounter with antigen takes place in T cell area of lymph node cortex *Antigen reached lymph node from infected tissue via afferent lymphatic vessel *B cell is activated by CD4 T-cell in T-cell area *Activated B cells *Migrate to medulla area and differentiate into plasma cells *Migrate to primary follicle to form germinal center *Migrate to medulla or bone marrow and complete differentiation into plasma cells *Develop into memory B cells

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30 B-LYMPHOCYTE TUMORS *Caused by mutations in genes that regulate cell growth *Genes regulating cell growth *Proto-oncogenes *Promotes cell growth *Tumor suppressor genes *Inhibits cells growth *Mutations in growth regulating genes *Transformation into oncogenes (cancer causing genes)

31 B LYMPHOCYTE TUMORS *Represents uncontrolled growth of single transformed B cell *Associated with all stages of development *Tumors retain characteristics of cell type and location *Hodgkin’s Lymphoma *Germinal center B cell in lymphoid tissue *Multiple myeloma *Plasma cell in bone marrow *Waldenstrom’s macroglobulinemia *IgM secreting B lymphocyte in lymphoid tissue *Burkitt’s lymphoma *Resembles germinal center B cell in lymphoid tissue

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33 HODGKIN’S DISEASE (LYMPHOMA) *Hodgkin’s disease is a type of lymphoma *Two types of lymphoma *Hodgkin’s disease *Non-Hodgkin’s lymphoma (NHL) *Two main types of Hodgkin’s disease *Classical (95%) *Nodular lymphocyte predominance (5%) *Disease most often starts in lymph nodes of upper body *Chest, neck or under the arms

34 HODGKIN’S DISEASE (LYMPHOMA) *Cause is not known but there are risk factors *Epstein-Barr Virus (EBV) infection *Geography *United States, Canada, northern Europe *Family history *Identical twin (very high) *Approximately 8,000 new cases each year in US *Cancer cells of HD are unique *Reed-Sternberg cells

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36 WALDENSTROM’S MACROGLOBULINEMIA *Indolent, non-Hodgkin’s lymphoma (NHL) *Classified as *Monoclonal gammopathy *Cancer cells *Features of B-cells and plasma cells *Lymphoplasmacytoid *Located primarily in bone marrow *Produce large amounts of monoclonal protein (antibody) *IgM *Approximately 1,500 new cases each year in US

37 MULTIPLE MYELOMA *Aggressive, non-Hodgkin lymphoma *Classified as *Monoclonal gammopathy *Cancer cells *Abnormal plasma cells (myeloma cells) *Located primarily in bone marrow *Produce monoclonal proteins (antibody) *IgG, IgA, free kappa or lambda light chains *Approximately 20,000 cases in US for 2008

38 BURKITT’S LYMPHOMA *B cell tumor with 2 forms *Endemic (African) *Facial tumors *Strongly associated with EBV infection *Nonendemic (Sporadic) *Abdominal tumors *Characteristic translocation *MYC proto-oncogene on chromosome 8 to IG genes *Chromosome 14 (90%) *Chromosomes 2 and 22 (10%) *MYC protein *Normally regulates cell division *Control is lost following translocation to IG gene

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42 CASE STUDY – 21 YEAR OLD MALE *21 year old WM presents with *Fever (102 F) *Sore throat *Moderate malaise, myalgia and fatigue *Difficulty in swallowing *H and P *Healthy and sexually active *Bilateral anterior and posterior cervical lymphadenopathy *Pharyngeal inflammation *Mild splenomegaly and no jaundice

43 CASE STUDY – 21 YEAR OLD MALE *Admitted to MC and administered *Penicillin G *Prednisone *Valacyclovir *Laboratory tests *CBC with diff *Liver function tests *Monospot test (Heterophile antibody) *Erythrocyte sedimentation rate (ESR) *Group A streptococcus antigen

44 CASE STUDY – 21 YEAR OLD MALE *CBC with diff *WBC 12.5 [ ] K/uL *RBC 4.0 [ ] M/uL *Platelets 250 [ ] K/uL *Hemoglobin 14.0 [ ] g/dL *Hematocrit 40 [ ] % *Neutrophils 45 [40-74] % *Lymphocytes 55 [15-47] % *Atypical lymphocytes 18 % *Monocytes 12 [0-12] %

45 REACTIVE (ATYPICAL) LYMPHOCYTES *Larger in size *Up to 30 um in diameter *More cytoplasm *Less dense nuclear chromatin *Irregular shaped nucleus *Nucleous may be present *Periphery of cell show “scalloped edge”

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47 CASE STUDY – 21 YEAR OLD MALE *Liver function tests *ALT 130 [19-55] U/L *AST 112 [15-37] U/L *Alk phos 150 [50-136] U/L *ESR 40 [0-30] mm/hr *GAS antigen Negative [Negative] *Monospot test Positive [Negative]

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50 CASE STUDY – 21 YEAR OLD MALE *Patient discharged after 36 hours *Treatment *NSAID *Recommendations *Avoid sports *Avoid alcohol

51 CASE STUDY – 18 YEAR OLD FEMALE *18 year old HF presents with *Fever (101 F) *Sore throat *Moderate malaise, myalgia and fatigue *Difficulty in swallowing *H and P *Healthy and sexually active *Bilateral anterior and posterior cervical lymphadenopathy *Pharyngeal inflammation *Mild splenomegaly and no jaundice

52 CASE STUDY – 18 YEAR OLD FEMALE *Admitted to MC and administered *Penicillin G *Prednisone *Valacyclovir *Laboratory tests *CBC with diff *Liver function tests *Monospot test (Heterophile antibody) *Erythrocyte sedimentation rate (ESR) *Group A streptococcus antigen

53 CASE STUDY – 18 YEAR OLD FEMALE *CBC with diff *WBC 13.5 [ ] K/uL *RBC 4.2 [ ] M/uL *Platelets 260 [ ] K/uL *Hemoglobin 14.5 [ ] g/dL *Hematocrit 42 [ ] % *Neutrophils 46 [40-74] % *Lymphocytes 56 [15-47] % *Atypical lymphocytes 20 % *Monocytes 12 [0-12] %

54 CASE STUDY – 18 YEAR OLD FEMALE *Liver function tests *ALT 136 [19-55] U/L *AST 115 [15-37] U/L *Alk phos 156 [50-136] U/L *ESR 42 [0-30] mm/hr *GAS antigen Negative [Negative] *Monospot test Negative [Negative]

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56 CASE STUDY – 18 YEAR OLD FEMALE *Epstein-Barr Virus serology (IFA) *Viral capsid antigen (VCA) IgM 1:320 [< 1:20] *Viral capsid antigen (VCA) IgG 1:40 [< 1:10] *Early antigen (D + R) IgG 1:20 [< 1:10] *Nuclear antigen (NA) IgM 1:80 [< 1:10] *Nuclear antigen (NA) IgG < 1:10 [< 1:10]

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58 CASE STUDY – 18 YEAR OLD FEMALE *Patient discharged after 24 hours *Treatment *NSAID *Recommendations *Avoid sports *Avoid alcohol

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61 CASE STUDY – 24 YEAR OLD FEMALE *24 year old WF presents with *Fever (101 F) *Moderate malaise and fatigue *Myalgia and bone pain *Shortness of breath *H and P *No significant history *Generalized lymphadenopathy *Pallor *Mild splenomegaly and no jaundice

62 CASE STUDY – 24 YEAR OLD FEMALE *Admitted to MC with diagnosis of *Pneumonia and anemia *Laboratory tests *CBC with diff *Monospot test (Heterophile antibody) *Pregnancy test *Influenza A and B antigens

63 CASE STUDY – 24 YEAR OLD FEMALE *CBC with diff *WBC 44.4 [ ] K/uL *RBC 1.0 [ ] M/uL *Platelets 8 [ ] K/uL *Hemoglobin 3.6 [ ] g/dL *Hematocrit 11.3 [ ] % *Neutrophils 6 [40-74] % *Lymphocytes 10 [15-47] % *Atypical lymphocytes 0 % *Monocytes 20 [0-12] % *Blasts 55 %

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67 CASE STUDY – 24 YEAR OLD FEMALE *Pregnancy test Negative [Negative] *Influenza antigens Negative [Negative] *Monospot test Positive [Negative] *Peripheral blood smear *RBCs showing anisopoikocytosis. Leukocytes show predominance of blasts many with cytoplasmic granules. Mature granulocytes show dysplastic features. Monocytes are atypical.

68 CASE STUDY – 20 YEAR OLD FEMALE *20 year old WF presents to ED c/o *Chest pain *POCT *Troponin [< 0.7] ng/mL *CK MB 44.8 [< 3.6] ng/mL *CK, Total 611 [21 – 215] U/L *Admitted to MC with diagnosis of *STEMI (ST segment elevation myocardial infarction) *Transported to Cardiac Catheterization Laboratory

69 CASE STUDY – 20 YEAR OLD FEMALE *History and Physical *Leg and hip pain 1 day prior *Diagnosis of IM 1 month prior *CBC with DIFF *WBC 8.6 [ ] K/uL *RBC 3.86 [ ] M/uL *Platelets 179 [ ] K/uL *Neutrophils 66 [40-74] % *Lymphocytes 24 [15-47] % *Monocytes 10 [0-12] %

70 CASE STUDY – 20 YEAR OLD FEMALE *Cardiac catheterization *Blockage of left anterior descending artery

71 CASE STUDY – 20 YEAR OLD FEMALE *Lipid profile *Cholesterol 134 [< 200] mg/dL *HDL 42 [> 40] mg/dL *LDL 74 [< 130] mg/dL *Triglycerides 90 [< 200] mg/dL *Homocysteine 5.6 [< 10.4] umol/L *Lipoprotein(a) 15 [< 75] mg/dL *Cardiolipin antibody Positive [Negative]

72 CASE STUDY – 20 YEAR OLD FEMALE *Mononucleosis test *Positive (strong) *EBV early antigen, IgG *Negative *CBC with DIFF *Normal

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