„Factor H and complement regulation” research group

 

Head of the research group

Members of the research group

 

Research interest

Our research concerns the complement system of innate immunity, particularly the function and regulation of the alternative complement pathway, the structure and function of factor H and factor H-related proteins. Complement is involved in the pathomechanism of several diseases. Dysregulation of the alternative pathway, polymorphisms and mutations in factor H or anti-factor H autoantibodies play a role in various diseases, including age-related macular degeneration (a leading cause of blindness in the Western world) and the kidney diseases atypical hemolytic uremic syndrome and dense deposit disease). Our main aim is to unveil the physiological roles of factor H and factor H-related proteins, in order to understand their role in diseases, which could then lead to tailored treatments in the future.
Keywords: innate immunity, complement system, autoimmunity, complement-mediated diseases, factor H protein family, pentraxins

 

Research projects

1. Interaction of factor H with immune cells.

Factor H is a major regulator of the alternative complement pathway. Its binding to receptors and influence on cellular functions, however, are poorly characterized. We recently showed that factor H, when bound to the human-pathogenic yeast Candida albicans, enhances the adhesion and activation of neutrophil granulocytes (Losse et al. 2010). In this project, we investigate the interaction of factor H with neutrophils, macrophages and dendritic cells.

Related publications:

  • Józsi M, Schneider AE, Kárpáti É, Sándor N. (2019) Complement factor H family proteins in their non-canonical role as modulators of cellular functions. Semin Cell Dev Biol. 85:122-131. (Review)
  • Schneider AE, Sándor N, Kárpáti É, Józsi M. (2016) Complement factor H modulates the activation of human neutrophil granulocytes and the generation of neutrophil extracellular traps. Mol Immunol. 72:37-48.
  • Svoboda E, Schneider AE, Sándor N, Lermann U, Staib P, Kremlitzka M, Bajtay Z, Barz D, Erdei A, Józsi M. (2015) Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CR4). Immunol. Lett. 168:13-21.
  • Losse J, Zipfel PF, Józsi M. (2010) Factor H and factor H-related protein 1 bind to human neutrophils via complement receptor 3, mediate attachment to Candida albicans, and enhance neutrophil antimicrobial activity. J. Immunol. 184:912-921.

 

2. Function of factor H-related proteins.

In addition to the complement inhibitor factor H, the factor H protein family includes five factor H-related (CFHR) molecules. In contrast to factor H, the function of the CFHRs is less characterized and controversial. Our aim is to understand the physiological role of the CFHR proteins and their association with certain diseases. We investigate their role in complement activation and interaction with pentraxins, which are soluble pattern recognition molecules of the innate immune system. We particularly analyze the interaction of CFHRs with the acute phase protein C-reactive protein and pentraxin 3 (PTX3), which is produced locally during inflammation and infection. CRP and PTX3 activate complement but also bind complement inhibitory molecules, such as factor H.

Related publications:

  • Cserhalmi M, Csincsi ÁI, Mezei Z, Kopp A, Hebecker M, Uzonyi B, Józsi M. (2017) The Murine Factor H-Related Protein FHR-B Promotes Complement Activation. Front Immunol. 8:1145.
  • Csincsi ÁI, Szabó Z, Bánlaki Z, Uzonyi B, Cserhalmi M, Kárpáti É, Tortajada A, Caesar JJE, Prohászka Z, Jokiranta TS, Lea SM, Rodríguez de Córdoba S, Józsi M. (2017) FHR-1 Binds to C-Reactive Protein and Enhances Rather than Inhibits Complement Activation. J Immunol. 199:292-303. 
  • Józsi M, Tortajada A, Uzonyi B, Goicoechea de Jorge E, Rodríguez de Córdoba S. (2015) Factor H-related proteins determine complement-activating surfaces. Trends Immunol. 36:374-384.
  • Csincsi ÁI, Kopp A, Zöldi M, Bánlaki Z, Uzonyi B, Hebecker M, Caesar JJ, Pickering MC, Daigo K, Hamakubo T, Lea SM, Goicoechea de Jorge E, Józsi M. (2015) Factor H-related protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation. J Immunol. 194:4963-4973.
  • Hebecker and Józsi. (2012) Factor H-related Protein 4 Activates Complement by Serving as a Platform for the Assembly of Alternative Pathway C3 Convertase via Its Interaction with C3b Protein. J. Biol. Chem. 2012 Jun 1;287(23):19528-19536.
  • Kopp et al. (2012) Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor H and factor H-related protein 1 to pentraxin 3. J. Immunol. 189:1858-1867.

 

3. Characterization of anti-factor H autoantibodies.

Dysregulation of the alternative complement pathway is implicated in the severe kidney diseases atypical hemolytic uremic syndrome and C3 glomerulopathies (including dense deposit disease). Some of the patients have circulating autoantibodies to factor H. Our aims are the detailed functional characterization and epitope mapping of the autoantibodies in order to understand their role in disease.

Related publications:

  • Nozal et al. (2016) Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome. Mol Immunol. 70:47-55.
  • Bhattacharjee A et al. (2015) The Major Autoantibody Epitope on Factor H in Atypical Hemolytic Uremic Syndrome Is Structurally Different from Its Homologous Site in Factor H-related Protein 1, Supporting a Novel Model for Induction of Autoimmunity in This Disease. J Biol Chem. 290:9500-9510.
  • Hofer J, Giner T, Józsi M. (2014) Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. Semin Thromb Hemost. 40:431-443.
  • Strobel et al. (2011) Factor H-related protein 1 neutralizes anti-factor H autoantibodies in autoimmune hemolytic uremic syndrome. Kidney Int. 80:397-404.
  • Strobel et al. (2010) Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome. Nephrol. Dial. Transplant. 25:136-144.
  • Józsi et al. (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood. 111:1512-1514.
  • Józsi et al. (2007) Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood. 110:1516-1518.

Applied methods:

  • recombinant protein expression
  • in vitro mutagenesis
  • ELISA
  • complement activation assays
  • SDS-PAGE and Western blot
  • flow cytometry
  • microscopy
  • surface plasmon resonance

Current grant support:

  • NKFI 125219, Functional studies on human complement factor H family proteins (2017-2021)
  • Institutional Excellence Program of the Ministry of Human Capacities of Hungary (2017-2020)
  • MTA, Roles of the complement system and possibilities of modulating complement activation (2019-2024)

Alumni:

Dr. Bánlaki Zsófia (2012-2013)

Brânduş Bianca (2017-2019)

Cserhalmi Marcell (2014-2019)

Dr. Csincsi Ádám István (2013-2017)

Kárpáti Éva (2015-2019)

Kovács Boglárka (2019-2020)

Dr. Kremlitzka Mariann (2018-2019)

Rabb Márton (2019-2020)

Dr. Szabó (Weiszhár) Zsóka (2014-2015)