Prof. Dr. Klaus Warnatz

Centre for Chronic Immundeficiency/
Division of Rheumatology and Clinical Immunology
University Medical Center Freiburg,
Breisacher Str 117
79106 Freiburg  

Tel. +49 (0) 761 270 77640
klaus.warnatz@uniklinik-freiburg.de

Project summary:

The origin and role of human CD21low B cells in autoimmune disease

Chronic activation of the immune system in the context of persistent infection or autoimmune reaction may lead to a phenomenon, which has been termed “exhaustion”. The term is used to describe a status of immune cells, which have undergone partial activation without achieving full effector function like cytotoxicity in the case of CD8 T cells or antibody production in the case of B cells. Although certain functions are impaired, these cells can still persist and potentially contribute to the local or systemic immune dysregulation. “Exhausted” B cells were first described in HIV as a subset of CD21low B cells of antiviral specificity. We had identified a similar B cell subset in autoimmune disease and in patients with common variable immunodeficiency (CVID). In CVID these CD21low B cells are mature, partially activated cells that have undergone several rounds of proliferation in vivo and fail to proliferate in vitro. Their response after BCR, CD40 and TLR signalling and the transcriptome examined ex vivo is severely altered compared to normal B cells. These cells are highly enriched at sites of inflammation as the lung in CVID or the joint in rheumatoid arthritis. In contrast to CVID patients, in patients with autoimmune disease most of the CD21low B cells have undergone class switch and belong to the memory pool. CD21low B cells cells show increased autoreactivity and residual antibody production.

In this project the origin, regulation and function of CD21low B cells in patients with systemic autoimmune disease and their contribution to the autoimmune dysregulation will be investigated and the findings will be compared with data from CD21low B cells of CVID patients.

Fig. 1 Top: CD21low B cells in a healthy control, one CVID patient and one patient suffering from systemic autoimmune disease. Bottom: Altered signalling in CD21low B cells.
Publications P 07:

Keller, B., Cseresnyes, Z., Stumpf, I., Wehr, C., Fliegauf, M., Bulashevska, A., Usadel, S., Grimbacher, B., Rizzi, M., Eibel, H., Niesner, R., and Warnatz, K (2016). Disturbed canonical nuclear factor of kappa light chain signaling in B cells of patients with common variable immunodeficiency. J Allergy Clin Immunol pii: S0091-6749(16)30441-9.

Voelxen, N., Wehr, C., Gutenberger, S., Keller, B., Erlacher, M., Dominguez-Conde, C., Bertele, D., Emmerich, F., Pantic, M., Jennings, S., Rakhmanov, M., Foerster, C., Martens, U. M., Platzbecker, U., Peter, H. H., Fisch, P., Boztug, K., Eibel, H., Salzer, U., and Warnatz, K. (2016). B-cell signaling in persistent polyclonal B lymphocytosis (PPBL). Immunol Cell Biol 94, 830-837.

Rakhmanov, M., Sic, H., Kienzler, A.K., Fischer, B., Rizzi, M., Seidl, M., Melkaoui, K., Unger, S., Moehle, L., Schmit, N.E., Deshmukh, S.D., Ayata, C.K., Schuh, W., Zhang, Z., Cosset, F.L., Verhoeyen, E., Peter, H.H., Voll, R.E., Salzer, U., Eibel, H., and Warnatz, K. (2014). High Levels of SOX5 Decrease Proliferative Capacity of Human B Cells, but Permit Plasmablast Differentiation. PloS one 9, e100328.

Unger, S., Seidl, M., Schmitt-Graeff, A., Bohm, J., Schrenk, K., Wehr, C., Goldacker, S., Drager, R., Gartner, B.C., Fisch, P., Werner, M. and Warnatz, K. (2014). Ill-Defined Germinal Centers and Severely Reduced Plasma Cells are Histological Hallmarks of Lymphadenopathy in Patients with Common Variable Immunodeficiency. J Clin Immunol 34, 615-626.

Visentini, M., Cagliuso, M., Conti, V., Carbonari, M., Mancaniello, D., Cibati, M., Siciliano, G., Giorda, E., Keller, B., Warnatz, K., et al. (2011). Telomere-dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency. Eur J Immunol 41, 854-862.

Foerster, C., Voelxen, N., Rakhmanov, M., Keller, B., Gutenberger, S., Goldacker, S., Thiel, J., Feske, S., Peter, H.H., and Warnatz, K. (2010). B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency. J Immunol 184, 7305-7313.

Rakhmanov, M., Keller, B., Gutenberger, S., Foerster, C., Hoenig, M., Driessen, G., van der, B.M., van Dongen, J.J., Wiech, E., Visentini, M., Deshmukh, S.D., Ayata, C.K., Schuh, W., Zhang, Z., Cosset, F.L., Verhoeyen, E., Peter, H.H., Voll, R.E., Salzer, U., Eibel, H., and Warnatz, K. (2009). Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc Natl Acad Sci U S A 106, 13451-13456.

Wehr, C., Kivioja, T., Schmitt, C., Ferry, B., Witte, T., Eren, E., Vlkova, M., Hernandez, M., Detkova, D., Bos, P.R., Poerksen, G., von, Bernuth H., Baumann, U., Goldacker, S., Gutenberger, S., Schlesier, M., Bergeron-van der, Cruyssen F., Le, Garff M., Debre, P., Jacobs, R., Jones, J., Bateman, E., Litzman, J., van Hagen, P. M., Plebani, A., Schmidt, R. E., Thon, V., Quinti, I., Espanol, T., Webster, A. D., Chapel, H., Vihinen, M., Oksenhendler, E., Peter, H. H., and Warnatz, K. (2008). The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 111, 77-85.

Wehr, C., Eibel, H., Masilamani, M., Illges, H., Schlesier, M., Peter, H.H., and Warnatz, K. (2004). A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol 113, 161-171.

Warnatz, K., Denz, A., Drager, R., Braun, M., Groth, C., Wolff-Vorbeck, G., Eibel, H., Schlesier, M., and Peter, H.H. (2002). Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 99, 1544-1551.