Navigation

AG Anja Lux

Focus of research: AG Anja Lux

The group of Dr. Anja Lux is interested in effector mechanisms of B cell depleting antibodies and Fc receptor dependent activation of immune cells.

Dr. Anja Lux

Interim Professorship for Integrated Immunology (Dr. Lux)

<< Staff of the Lux group >>

Therapeutic monoclonal antibodies (mAbs) directed against the CD20 surface marker of B cells e.g. Rituximab or Ofatumumab are widely used to treat malignant as well as inflammatory disorders in humans as they cause efficient depletion of CD20 expressing B cell populations. The effector mechanisms underlying CD20 mAb activity are discussed to involve the mononuclear phagocytic cells, NK cells or the complement system. However, CD20 mAb activity has predominantly been studied in mouse models or in vitro and the effector mechanisms in humans in vivo are still unclear.

One focus of our research is to fill this gap in knowledge by studying CD20 mAb induced B cell depletion in human immune system mice. These so-called humanized mice are characterized by the long-term presence of a wide spectrum of human hematopoietic cells including developmental precursor populations and therefore allow for analysis of human immunoglobulin G (IgG) in a human immune system in vivo. We thereby aim to identify immune effector cells involved in B cell depletion and characterize potential organ niches with reduced mAb activity (Figure 1).

 

Fig. 1. Humanized mice are generated by transplantation of immunodeficient mice with human hematopoietic stem cells isolated from umbilical cord blood (A). B cell depletion is induced by treatment with CD20-specific mAbs to determine mAb activity for B cell subpopulations in different organs as well as identify effector mechanisms of B cell depletion (B).

 

Figure 2. Overview of human type I (A) and type II (B) Fc receptors. FcRs differ in their affinity for IgG subclasses, their capacity to induce intracellular signaling upon ligand binding and expression profile on immune cell subsets. Figure adapted from Nimmerjahn F, Gordan S and Lux A, Trends in Immunology, 2015.

Most types of human immune cells express IgG binding Fc receptors (FcγR). By interacting with IgG, these FcγR are crucially involved in bridging innate and adaptive immune responses. FcγR come, however, in different flavours: They can initiate or dampen immune cell activation and they might be able to interact with monomeric IgG (high-affine CD64) or only with IgG in larger antibody-antigen immune complexes (low to medium affine CD32 and CD16). Most importantly, many immune cell subsets co-express different kinds of FcγRs to various degrees and the situation becomes even more complex due to the presence of so-called type II Fc receptors only recently recognized to interact with IgG.

 

To date, the individual contribution of FcR on different immune cell types and a potential cell-type specific receptor activity are largely unknown. Therefore, we currently study IgG immune complex binding to FcR and its effects on immune cell function with a focus on the role of immune complex size, IgG subclass and glycosylation and FcγR polymorphisms. Given that FcR are transmembrane- or membrane-anchored surface receptors, we further investigate if immune cell type specific plasma membrane environments affect FcR function.

The primary function of innate and adaptive immune cells is to protect us from invading pathogens. However, the same mechanisms involved in protective immune responses are also responsible for the pathogenesis of autoimmune diseases if the careful balance of immune cell activation and inhibition is disturbed. Surprisingly, the causative immune dysregulation may precede clinical manifestation of disease in humans by many years while the reasons for this phenomenon are still unknown. In a mouse model of inflammatory arthritis, we are currently investigating changes in innate immune cell function and their contribution to the switch from asymptomatic to symptomatic disease.

Anja Lux on Google Scholar

5 Key Publications

  1. Kara S, Amon L, Lühr JJ, Nimmerjahn F, Dudziak D, Lux A. Impact of plasma membrane domains on IgG Fc receptor function. Frontiers in Immunology. 2020.
  2. Kao D, Danzer H, Collin M, Groß A, Eichler J, Stambuk J, Lauc G, Lux A, Nimmerjahn F. A Monosaccharide Residue Is Sufficient to Maintain Mouse and Human IgG Subclass Activity and Directs IgG Effector Functions to Cellular Fc Receptors. Cell Rep. 2017. 47(12):2070-2079.
  3. Lux A, Seeling M, Baerenwaldt A, Lehmann B, Schwab I, Repp R, Meidenbauer N, Mackensen A, Hartmann A, Heidkamp G, Dudziak D, Nimmerjahn F. A humanized mouse identifies the bone marrow as a niche with low therapeutic IgG activity. Cell Rep. 2014. 7(1):236-48
  4. Lux A, Yu X, Scanlan CN, Nimmerjahn F. Impact of immune complex size and glycosylation on IgG binding to human FcγRs. J Immunol. 2013. 190(8):4315-23
  5. Lux A, Nimmerjahn F. Of mice and men: the need for humanized mouse models to study human IgG activity in vivo. J Clin Immunol. 2013. 33 Suppl 1:S4-8

Primary Publications (since 2012)

Danzer H, Glaesner J, Baerenwaldt A, Lux A, Harrer T, Gessner A, Nimmerjahn F. The human inhibitory Fc-receptor modulates early pathogen-specific versus self-reactive antibody responses in Lyme arthritis in humanized mice. eLife. doi: 10.7554/eLife.55319. 2020

Kara S, Amon L, Lühr JJ, Nimmerjahn F, Dudziak D, Lux A. Impact of plasma membrane domains on IgG Fc receptor function. Frontiers in Immunology. doi: 10.3389/fimmu.2020.01320. 2020.

Kallolimath S, Hackl T, Gahn R, Grünwald-Gruber C, Zich W, Kogelmann B, Lux A, Nimmerjahn F, Steinkellner H. Expression Profiling and Glycan Engineering of IgG Subclass 1-4 in Nicotiana benthamiana. Front Bioeng Biotechnol. doi: 10.3389/fbioe.2020.00825. 2020.

Klausz K, Cieker M, Kellner C, Rösner T, Otte A, Krohn S, Lux A, Nimmerjahn F, Valerius T, Gramatzki M, Peipp M. Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy. Haematologica. doi: 10.3324/haematol.2020.251371. 2020.

Schaffert A, Hanić M, Novokmet M, Zaytseva O, Krištić J, Lux A, Nitschke L, Peipp M, Pezer M, Hennig R, Rapp E, Lauc G, Nimmerjahn F. Minimal B Cell Extrinsic IgG Glycan Modifications of Pro- and Anti-Inflammatory IgG Preparations in vivo. Front Immunol. 10:3024. doi: 10.3389/fimmu.2019.03024. 2020

Gordan S, Albert H, Danzer H, Lux A, Biburger M, Nimmerjahn F. The Immunological Organ Environment Dictates the Molecular and Cellular Pathways of Cytotoxic Antibody Activity. Cell Rep. 29(10):3033-3046.e4. doi: 10.1016/j.celrep.2019.10.111. 2019

Grötsch B, Lux A, Rombouts Y, Hoffmann AC, Andreev D, Nimmerjahn F, Xiang W, Scherer HU, Schett G, Bozec A. Fra1 controls rheumatoid factor autoantibody production by bone marrow plasma cells and the development of autoimmune bone loss. J Bone Miner Res. doi: 10.1002/jbmr.3705. 2019

Robinett RA, Guan N, Lux A, Biburger M, Nimmerjahn F, Meyer AS. Dissecting FcγR Regulation through a Multivalent Binding Model. Cell Syst. 2018. 7(1):41-48

Stopforth RJ, Oldham RJ, Tutt AL, Duriez P, Chan HTC, Binkowski BF, Zimprich C, Li D, Hargreaves PG, Cong M, Reddy V, Leandro MJ, Cambridge G, Lux A, Nimmerjahn F, Cragg MS. Detection of Experimental and Clinical Immune Complexes by Measuring SHIP-1 Recruitment to the Inhibitory FcγRIIB. J Immunol. 2018. 200(5):1937-1950

Kao D, Lux A, Schaffert A, Lang R, Altmann F, Nimmerjahn F. IgG subclass and vaccination stimulus determine changes in antigen specific antibody glycosylation in mice. Eur J Immunol. 2017. 47(12):2070-2079

Lee CH, Romain G, Yan W, Watanabe M, Charab W, Todorova B, Lee J, Triplett K, Donkor M, Lungu OI, Lux A, Marshall N, Lindorfer MA, Goff OR, Balbino B, Kang TH, Tanno H, Delidakis G, Alford C, Taylor RP, Nimmerjahn F, Varadarajan N, Bruhns P, Zhang YJ, Georgiou G. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions. Nat Immunol. 2017. 18(8):889-898

Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Magorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y, Koeleman CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G, Krönke G. Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol. 2017. 18(1):104-113

Heidkamp GF, Sander J, Lehmann CHK, Heger L, Eissing N, Baranska A, Lühr JJ, Hoffmann A, Reimer KC, Lux A, Söder S, Hartmann A, Zenk J, Ulas T, McGovern N, Alexiou C, Spriewald B, Mackensen A, Schuler G, Schauf B, Forster A, Repp R, Fasching PA, Purbojo A, Cesnjevar R, Ullrich E, Ginhoux F, Schlitzer A, Nimmerjahn F, Schultze JL, Dudziak D. Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment. Sci Immunol. 2016. 1(6)

Nimmerjahn F, Gordan S, Lux A. FcγR dependent mechanisms of cytotoxic, agonistic, and neutralizing antibody activities. Trends Immunol. 2015. 36(6):325-36

Kao D, Danzer H, Collin M, Groß A, Eichler J, Stambuk J, Lauc G, Lux A, Nimmerjahn F. A Monosaccharide Residue Is Sufficient to Maintain Mouse and Human IgG Subclass Activity and Directs IgG Effector Functions to Cellular Fc Receptors. Cell Rep. 2015

Schwab I, Lux A, Nimmerjahn F. Pathways Responsible for Human Autoantibody and Therapeutic Intravenous IgG Activity in Humanized Mice. Cell Rep. 2015 13(3):610-620

Harre U, Lang SC, Pfeifle R, Rombouts Y, Frühbeißer S, Amara K, Bang H, Lux A, Koeleman CA, Baum W, Dietel K, Gröhn F, Malmström V, Klareskog L, Krönke G, Kocijan R, Nimmerjahn F, Toes RE, Herrmann M, Scherer HU, Schett G. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun. 2015. 6:6651

Lux A, Nimmerjahn F. No Need for Constant Help: Human IgG2 Antibodies Have an Autonomous Agonistic Activity for Immunotherapy of Cancer. Cancer Cell. 2015. 27(1):10-1

Yamada DH, Elsaesser H, Lux A, Timmerman JM, Morrison SL, de la Torre JC, Nimmerjahn F, Brooks DG. Suppression of Fcg-Receptor-Mediated Antibody Effector Function during Persistent Viral Infection. Immunity. 2015. 42(2):379-390

Lux A, Seeling M, Baerenwaldt A, Lehmann B, Schwab I, Repp R, Meidenbauer N, Mackensen A, Hartmann A, Heidkamp G, Dudziak D, Nimmerjahn F. A humanized mouse identifies the bone marrow as a niche with low therapeutic IgG activity. Cell Rep. 2014. 7(1):236-48

Toh ML, Bonnefoy JY, Accart N, Cochin S, Pohle S, Haegel H, De Meyer M, Zemmour C, Preville X, Guillen C, Thioudellet C, Ancian P, Lux A, Sehnert B, Nimmerjahn F, Voll RE, Schett G. A CSF-1 receptor monoclonal antibody has potent bone and cartilage protective effects in experimental arthritis. Arthritis Rheumatol. 2014. 66(11):2989-3000

Biburger M, Lux A, Nimmerjahn F. How immunoglobulin G antibodies kill target cells: revisiting an old paradigm. Adv Immunol. 2014. 124:67-94

Kao D, Lux A, Schwab I, Nimmerjahn F. Targeting B cells and autoantibodies in the therapy of autoimmune diseases. Semin Immunopathol. 2014. 36(3):289-99

Schwab I, Lux A, Nimmerjahn F. Reply to – IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. Nat Rev Immunol. 2014. 14(5):349

Nimmerjahn F, Lux A. LILR-B1 blocks activating FcγR signaling to allow antibody dependent enhancement of dengue virus infection. Proc Natl Acad Sci U S A. 2014. 111(7):2404-5

Seeling M, Hillenhoff U, David JP, Schett G, Tuckermann J, Lux A, Nimmerjahn F. Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. Proc Natl Acad Sci U S A. 2013. 110(26):10729-34

Lux A, Yu X, Scanlan CN, Nimmerjahn F. Impact of immune complex size and glycosylation on IgG binding to human FcγRs. J Immunol. 2013. 190(8):4315-23

Lux A, Nimmerjahn F. Of mice and men: the need for humanized mouse models to study human IgG activity in vivo. J Clin Immunol. 2013. 33 Suppl 1:S4-8

Böhm S, Schwab I, Lux A, Nimmerjahn F. The role of sialic acid as a modulator of the anti-inflammatory activity of IgG. Semin Immunopathol. 2012. 34(3):443-53

Lehmann B, Schwab I, Böhm S, Lux A, Biburger M, Nimmerjahn F. FcγRIIB: a modulator of cell activation and humoral tolerance. Expert Rev Clin Immunol. 2012. 8(3):243-54

Research of the Lux group is funded in the context of the following projects:

  • DFG FOR2886/B2: Die IgG-Glykosylierung in der Regulation der rheumatoiden Arthritis (2019-2021)
  • DFG GRK2504/C5: Inducing long-lasting HIV Env-specific antibody responses by intrastructural help (2019-2024)
  • DFG GRK2599/P4: Regulation of immune complex-mediated DC-dependent immune responses by DCIR (2020-2025)