Prof. Dr. Klaus Warnatz

Centre for Chronic Immundeficiency/
Division of Rheumatology and Clinical Immunology
University Medical Center Freiburg,
Breisacher Str 115
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:

Reincke, M., Payne, K.J., Harder, I., Strohmeier, V., Voll, R.E., Warnatz, K.* and Keller B.* (2020). The Antigen Presenting Potential of CD21low B cells. Front. Immunol. 3, 210.   *equal contribution

Freudenhammer, M., Voll, R.E., Binder, S.C., Keller, B.*, and Warnatz, K*. (2020). Naive- and Memory-like CD21(low) B Cell Subsets Share Core Phenotypic and Signaling Characteristics in Systemic Autoimmune Disorders. J. Immunol. 205, 2016-2025.   *equal contribution

Cossarizza, A., Chang, H.D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W.W., Aghaeepour, N., Akdis, M., Allez, M., Keller, B., … Warnatz, K., et al. (2019). Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur. J. Immunol. 49, 1457-1973.

Keller, B.*, Shoukier, M.*, Schulz, K., Bhatt, A., Heine, I., Strohmeier, V., Speckmann, C., Engels, N., Warnatz, K., and Wienands, J. (2018). Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency. J. Exp. Med. 215, 1327-1336.   *equal contribution

Unger, S., Seidl, M., van Schouwenburg, P., Rakhmanov, M., Bulashevska, A., Frede, N., Grimbacher, B., Pfeiffer, J., Schrenk, K., Munoz, L., … Keller, B., and Warnatz, K. (2018). The TH1 phenotype of follicular helper T cells indicates an IFN-gamma-associated immune dysregulation in patients with CD21low common variable immunodeficiency. J. Allergy Clin. Immunol. 141, 730-740.

Keller, B., Stumpf, I., Strohmeier, V., Usadel, S., Verhoeyen, E., Eibel, H., and Warnatz, K. (2017). High SYK Expression Drives Constitutive Activation of CD21(low) B Cells. J. Immunol. 198, 4285-4292.

Keller, B., Cseresnyes, Z., Stumpf, I., Wehr, C., Fliegauf, M., Bulashevska, A., Usadel, S., Grimbacher, B., Rizzi, M., Eibel, H., … 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. 139, 220-231.e8.

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.