Case of the Month

Discussion

CD19+/CD20+ cells (B1a cells) after allogeneic hematopoietic stem cell transplant:

The B-Lymphocytes are comprised approximately 10% of peripheral blood lymphocytes. In adult humans, the majority of peripheral B-cells are B-2 cells, which function as humeral adaptive immune system by secreting antibodies. B-1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response, but are not part of the adaptive immune system as they have no memory. However, B-1 cells constitute the majority of B cells in fetal life and infancy, and can be divided into two subgroups; B-1a (CD5 positive) and B-1b (CD5 negative).

B2 cells (Mature B cells):

B-2 cells develop from late neonatal life onwards, are negatively selected by recognition of self-antigens and are generated in bone marrow throughout life. They circulate throughout the blood and secondary lymphoid tissues.

Follicular and marginal zone B cells both arise from the B2 lineage and can respond to a broad range of T-dependent (TD) and T-independent antigens.

B2 cells can undergo class switching, somatic hypermutation, and generate memory cells, thereby potentially providing long-lived antibody-mediated protection against many structurally diverse pathogens.

B1 cells:

B1 cells are considered innate immune cells that produce the majority of “natural” immunoglobulin M (IgM) and IgA, which is largely encoded by germline immunoglobulin genes. Because of its polyreactivity and ability to recognize large repetitive structures, this natural IgM acts as a first line of defense against pathogens such as encapsulated polysaccharide-expressing bacteria.

B1 cells predominate during fetal and neonatal development, self renew following their generation from stem cells present at these early stages of life, and decline by age. In adults they predominantly localize to peritoneal and pleural cavities.

B1 cells have characteristic phenotype of CD20+, CD27+, CD43+, CD70-, CD11b+, sIgM++, sIgD+ and can be divided into two subtypes¹:

• B1a (CD5+): Spontaneously producing broadly reactive natural IgM.
• B1b (CD5-): Can generate T-independent, long-lasting IgM responses to some infectious pathogens².

Some studies showed that CD5+ cells (B1a cells) in adult could compromise 10-25% of B-cells in blood³, 10-30% in tonsils⁴ and approximately 10% of B-cells in spleen. However, B1a cells are primarily found in the peritoneal cavity and develop and persist as self-replenishing population.

The weak auto-reactivity of the B-1a cells has been postulated to play a role in autoimmune pathogenesis such as rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematous⁵. Increase B1a cells also has been reported in some patients with HCV hepatitis⁶.

Only few data are available in the literature regarding increase B-1a cells population after allogeneic bone marrow transplantation in adults with hematological malignancies.

B1a cells after bone marrow transplant patients:

Studies demonstrate that a high number of polyclonal CD5+ B cells (B1a cells)⁷ could be increased up to 20% of total cells even after 18 months of transplantation⁸ and will return to the normal level after 2 years post transplant². It is important that they should not be confused with an atypical CD5+ lymphoproliferative disorder⁹. Physiological B-1a cells are distinguishable from the abnormalCD19+CD5+B-CLL cells by different fluorescence patterns (Polyclonal CD19+bright, CD5+dim-to-bright and Monoclonal CD19+dim, CD5+dim, respectively). Some authors have described these B1a cells as CD5+ normal stage 3 hematogones¹⁰, which can increase after the bone marrow transplant.

References

1. Daniel O. Griffin, Nichol E. Holodick, and Thomas L. Rothstein. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+CD27+CD43+CD70−. J Exp Med. 2011 Jan 17; 208(1): 67–80. doi:  10.1084/jem.20101499
2. Dino Veneri, Massimo Franchini, Donata de Sabata, Silvia Ledro, Antonio Vella, Riccardo Ortolani, Giovanni Pizzolo, and Fabio Benedetti. Peripheral blood CD5-positive B lymphocytes (B-1a cells) after allogeneic stem cell transplantation for acute myeloid leukaemia in humans. Blood Transfus. 2008 Oct; 6(4): 220–224. doi:  10.2450/2008.0010-08
3. Youinou P, Jamin C, Lydyard PM. CD5 expression in human B-cell populations. Immunol Today. 1999 Jul; 20(7):312-6.
4. Dono, M., Burgio, V. L., Tacchetti, C., Favre, A., Augliera, A., & Zupo, S. et al., (1996). Subepithelial B cells in the human palatine tonsil. I. Morphologic, cytochemical and phenotypic characterization. European Journal of Immunology, 26, 2035– 2042.
5. Youinou, P., & Lydyard, P. M. (2001). CD5+ B cells in nonorgan-specific autoimmune diseases: a fresh look. Lupus,10, 523–525.
6. Zuckerman, E., Slobodin, G., Kessel, A., Sabo, E., Yeshurun, D., & Halas, K. et al., (2002). Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection. Clinical and Experimental Immunology, 128, 353– 358.
7. Moins-Teisserenc H, Busson M, Herda A, Apete S, Peffault de Latour R, Robin M, Xhaard A, Toubert A, Socié G. CD19+CD5+ B cells and B1-like cells following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013 Jun;19(6):988-91. doi: 10.1016/j.bbmt.2013.03.006. Epub 2013 Mar 16.
8. Antin JH, Ault KA, Rappeport JM, Smith BR. B lymphocyte reconstitution after human bone marrow transplantation: leu-1 antigen defines a distinct population of B lymphocytes. J Clin Invest. 1987;80:325-332.
9. Robert A. Hillard, Lazaros J. Lekakis, Joseph F. Pulliam. Increased polyclonal CD5+ B1a lymphocytes in a haploidentical stem cell transplant recipient. Cytometry Part B - Clinical Cytometry, Mar 1, 2011,  page 119-121
10. Fuda FS1, Karandikar NJ, Chen W. Significant CD5 expression on normal stage 3 hematogones and mature B Lymphocytes in bone marrow. Am J Clin Pathol. 2009 Nov;132(5):733-7. doi: 10.1309/AJCPU5E3NXEKLFIY.