AG Prof. Dr. Matthias Mack

We have identified the previously obscure antigen-capturing cells as basophils. In pre-immunized mice only two cell populations are able to bind (capture) significant amounts of antigen on their cell surface. These are antigen-specific B cells that capture the antigen by their specific B cell receptor; and basophils that capture antigens by antigen-specific IgE bound to the high affinity FceRI-receptor. Binding of antigens activates basophils to immediately release IL-4 and IL-6 (in mice). During a secondary (memory) immune response basophils are responsible for the immediate production of IL-4 following injection of the antigen. This leads to an enhancement of humoral memory immune responses. Also in primary immune responses basophils constitute an important source of IL-4 as basophils can also be activated by various cytokines and other molecules like proteases from parasites. Thus basophils are an important source for the initial IL-4 which is required to induce a Th2 differentiation. By enhancement of humoral and Th2 immune responses, basophils play an important role in diseases like rheumatoid arthritis and lupus nephritis. Due to the profibrotic properties of IL-4 basophils are also involved in fibrogenesis, as shown in a model of chronic transplant rejection.  We currently further analyze the role of basophils in autoimmunity and fibrosis.

IL-3 belongs to the family of hematopoietic cytokines including GM-CSF and IL-5. For many years IL-3 was considered to be mainly involved in hematopoiesis and defense against parasites. We have identified IL-3 as an essential cytokine in systemic lupus erythematodes (SLE), rheumatoid arthritis and multiple sclerosis and demonstrate that T cells are the main source of IL-3 in murine models of inflammation. Blockade of IL-3 with an antibody or genetic deletion of IL-3 markedly improved disease activity in mouse models for systemic lupus (MRL-lpr), rheumatoid arthritis (collagen-induced arthritis, CIA) and multiple sclerosis (experimental autoimmune encephalitis, EAE). We and others found that IL-3 is an essential inductor cytokine for several classical proinflammatory cytokines, like IL-6, TNF-alpha and IL-1. In addition, IL-3 is essential for mobilization of innate immune cells from the bone marrow during inflammation. Thus, blockade of IL-3 interferes with multiple proinflammatory mechanisms explaining the superior efficacy of inhibitory IL-3 antibodies. Blockade or deficiency of IL-3 is very well tolerated in mice. In contrast, injection of recombinant IL-3 significantly increased disease activity in mouse models and induced polyarthritis in healthy rhesus monkeys.

In humans, IL-3 activates plasmocytoid dendritic cells (pDC), monocytes, basophils, mast cells, B cells and endothelial cells. Plasmacytoid dendritic cells are the most important producers of type I interferons that play a central role in the pathogenesis of systemic lupus. Also monocytes and B cells importantly contribute to autoimmune diseases in humans. In endothelial cells IL-3 induces the upregulation of E- and P-selectins and thus enables the transendothelial migration of leukocytes. We have generated multiple monoclonal antibodies against human IL-3 and currently analyze the expression of IL-3 in patients with autoimmune and inflammatory diseases. We also evaluate the potential of these antibodies for treatment of patients.

Mouse and human monocytes can be divided into CCR2+ and CCR2- monocytes. The majority of monocytes is CCR2+ and is frequently found in inflamed tissue. Using a variety of animal models and antibodies to specifically deplete these cells we and others have shown that CCR2+ monocytes are critically involved in inflammation and tissue destruction. We currently develop new tools to specifically deplete CCR2+ monocytes in patients with inflammatory and autoimmune diseases.

During recent years we and others have established that collagen-producing cells in the kidney can be derived from various cellular sources, including resident mesenchymal fibroblasts, pericytes, bone marrow-derived cells, tubular epithelial cells and endothelial cells. Collagen producing bone marrow derived cells are frequently called fibrocytes. We investigate to what extent fibrocytes contribute to renal fibrosis, how they migrate into the kidney and how they are activated to produce collagen. We also study the functional relevance of cell-type specific collagen-production in the kidney.

• Mack, M., Riethmüller, G. & Kufer, P. A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc Natl Acad Sci U S A 92, 7021-7025 (1995).
• Mack, M. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med 6, 769-775 (2000).
• Mack, M. et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J Immunol 166, 4697-4704 (2001).
• Denzel, A. et al. Basophils enhance immunological memory responses. Nat Immunol 9, 733-742 (2008).
• Niedermeier, M. et al. CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci U S A 106, 17892-17897 (2009).
• Renner, K. et al. IL-3 contributes to development of lupus nephritis in MRL/lpr mice. Kidney Int 88, 1088-1098 (2015).
• Renner, K. et al. IL-3 promotes the development of experimental autoimmune encephalitis. JCI Insight 1, e87157 (2016).
• Buchtler, S. et al. Cellular Origin and Functional Relevance of Collagen I Production in the Kidney. J Am Soc Nephrol 29, 1859-1873 (2018).
• Balam, S. et al. IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils. J Immunol 202, 3514-3523 (2019).
• Renner, K. et al. Severe T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes. Nature communications 12, 3006 (2021).