Complement is an important immune recognition and defence system that is central for homeostasis and that directs the anti-inflammatory immune response in humans.

The Department of Infection Biology studies how complement, as the central part of innate immunity, controls infectious microbes and contributes to the pathology of human diseases. We study how the human pathogenic yeast Candida albicans evades host complement attack and consequently causes infections. The research group Immunoregulation studies how complement together with macrophages controls the immune response and how complement drives the inflammatory response of these phagocytic cells.

The complement system regulates and controls immune homeostasis. Genetic modifications such as mutations, sequence and copy number variation cause several disorders that manifest in different organs, primarily in the kidney and in the retina of the eye. The identification of novel autoantibodies, as well as new disease-related genetic variants contributed to the better understanding of the pathology of two complement mediated kidney disorders. These results formed the bases for the development of new diagnostic and also new therapeutic approaches for the autoimmune kidney diseases DEAP-HUS and MPGN II/ DDD/C3G.

The human pathogenic yeast Candida albicans shields its surface from the immune attack of the human host and protects itself from the destructive action of the activated immune system. Candida expresses specific surface proteins which mimic host surface structures and which bind specific soluble human immune and complement regulators from human plasma. With this surface modification Candida uses a ‘wolf in sheep’s clothing’ approach – this means the fungal pathogen Candida is invisible for the host immune system. In consequence, the fungus can control, modulate, block and inhibit host immune reactions. Thereby, the human pathogen can propagate in the immunocompetent host and cause an infection.

Candida albicans responds and modulates host innate as well as adaptive immune reactions. This project aims at elucidating the mechanisms of immune responses by human monocytes and macrophages as well as B cells to Candida. Microbial proteins will be investigated that alone or together with recruited human plasma proteins modulate opsonization, cell interaction and activation. In human plasma, Candida activates all three complement pathways, the alternative, the classical and the lectin pathway. The complement activation product C3b is deposited onto the Candida surface to mark the foreign cells for phagocytosis and for the recognition by different immune cells. C3b and the cleavage products iC3b and C3d are ligands of different cellular receptors. C3b and iC3b are the natural ligands of complement receptors CR3 and CR4 expressed on human monocytes and macrophages. In combination with co-receptors, the monocytes are activated and differentiate into an inflammatory or a regulatory type of macrophage. C3d is the natural ligand of CR2 on B cells and coligation with the B cell antigen results in augmented signaling as a result of the redistribution of the entire coreceptor complex to the lipid rafts. Candida expresses proteins that modulate complement mediated opsonization on different levels and subsequently also the interaction and activation of immune cells. The characterization of the molecular and the cellular interplay, on the level of single molecules and cells, will be carried out and developed into a bioinformatics-based infection model that will offer novel therapeutic targets for treatment.

Complement as the central homeotic system of mammals and as the first defense line of innate immunity recognizes, attacks, damages and ultimately eliminates foreign invaders. These infectious microbes are eliminated by the host immune attack but in contrast pathogenic microbes escape the host immune attack. The innate immune response of the human host acts directly and immediately and all infectious pathogens including fungi, Gram negative-, as well as Gram positive bacteria, and protozoa always face the same innate immune response. In order to survive and to establish an infection in such an immunocompetent host, all these diverse pathogens have evolved evasion strategies to combat, control and inactivate the damaging and destructive host innate immune and complement response. The Department of Infection Biology analyses the immune evasion response of pathogenic Gram positive bacteria, including Staphylococcus aureus, Streptococcus pneumonia, andGram negative bacteria such as Pseudomonas aeruginosa, Borrelia burgdorferi, pathogenic fungi and Plasmodium falciparum. One aspect of our work is to identify central microbial immune evasion proteins and virulence factors and to define their molecular mode of action. In addition, we are interested  in identifying common evasion principles used and shared by the pathogenic microbes to combat host innate immune response and complement attacks. Identifying and defining the action of proteins involved in this intense immune interaction and understanding how these molecules interact is of relevance to develop new control strategies.

The effector function of the activated complement system on the surface of intact  autologous cells is tightly controlled and regulated. The Department of Infection Biology characterizes a family of human immune- and complement regulators termed Factor H Protein Family. This protein family with seven members includes Factor H as the central regulator, FHL1 which is encoded by an alternatively spliced transcript derived from the Factor H gene as well as five CFHR proteins (Complement Factor H related proteins) CFHR1 – CFHR5. CFHR represent unique innate immune regulators and the corresponding genes are positioned in a gene cluster which is located in close chromosomal proximity to the Factor H gene. Genetic variations in form of mutations, gene polymorphisms and copy number variations in the Factor H-CFHR1 gene cluster on the human chromosomes 1q32 are associated with several human diseases including the kidney disorders Hemolytic Uremic Syndrome (HUS) and Membranoproliferative Glomerulonephritis, (MPGN) also termed C3 glomerulopathy, as well as IgA Nephropathy, AMD (Age related macular degeneration ) a frequent form of blindness in elderly people of the western world and SLE (Systemic Lupus Erythematosus). Certain genetic scenarios like the common deletion of the CFHR3-CFHR1 genes occur in the healthy population and  have a protective role in AMD and IgA nephropathy but the same genetic constellation results confers risk for the autoimmune form of HUS and for SLE. For immune evasion of pathogenic fungi and microbes and in disease pathology, the functional characterization  of the infection is central for defining the understanding of the exact role of the individual proteins involved in the immune process. In addition, the interplay between the members of this protein family helps to define how these proteins switch and direct the immune and complement response.

Hemolytic uremic syndrome (HUS) is a rare disease which affects mostly small vessels and arteries of the human body, which are occluded by thrombi and in which the endothelial lining of the vessels is damaged. Thereby, the blood flow is blocked and the surrounding tissue is not properly supplied with nutrients and oxygen. HUS frequently affects the vessels or arteries in the kidney, however, other organs and tissues  may also be involved. HUS has different causes and triggers. Infections with enterohemorrhagic Escherichia coli (EHEC)  are a frequent cause of the disease  and are associated with gene mutations which affect regulators and components of the complement system. A third form includes the formation of autoantibodies which are frequently directed to the C terminal recognition region of the complement regulator Factor H. Most juvenile patients develop autoantibodies on bases of the homozygous deletion of a chromosomal segment, which includes the human CFRH3-CFHR1 genes. Understanding the various causes that result in pathology is relevant to define disease severity, to identify variants of the disease, to differentiate the prognosis for therapy and for the function of a transplanted kidney.

Membranoproliferative Glomerulonephritis (MPGN) is a rare kidney disorder which most frequently affects young patients. This disease which is currently also termed C3 glomerulopathy represents a spectrum of related disorders. The major diagnosis is based on the immunohistological evaluation of a kidney biopsy.The involvement of complement and autoimmune parameters such as the C3 nephritic factor, autoantibodies to Factor B, Factor H and to the C3 convertase  have frequently been reported. In addition, genetic mutations including the genes Factor H, C3 and the CFHR genes, i.e. CFHR2, CFHR5 and CFHR3 are reported in patients with MPGN /C3G. The Department of Infection Biology is interested in understanding the exact role of complement in the pathomechanisms of this severe kidney disorder. Our central aim is to understand the scenarios that result in the formation of autoimmune forms. In addition, we aim at defining how the various genetic alterations result in pathology and the heterogeneity of this disease. To allow a better understanding of the heterogeneity and pathophysiology we have established a registry that currently includes more than 250 patients suffering from the initial diagnosis MPGN I, or MPGNII. This allows us to define subtypes of the heterogeneous disease. Individual auto antibodies and mutant proteins are characterized to show how they affect and disrupt immune homeostasis. Using this approach and in close collaboration with clinical and medical doctors, new forms of diagnosis and therapy are being developed with regard to these severe kidney diseases.

The complement system is a major part of innate immunity and plays an essential role in cellular homeostasis, tissue remodeling, as well as in host defense and inflammation. Deregulated complement action or activation due to absent or defective complement regulators have been implicated in diseases like age-related macular degeneration (AMD) or C3-glomerulopathy (C3G). The aim of this research project is to identify and characterize novel human complement regulators and to investigate the role of these regulators in the disease pathology of AMD. AMD is the most common cause of blindness in developed countries. The disease is characterized by the degeneration of RPE cells due to the accumulation of drusen at the macular. The ARMS2 (age-related maculopathy susceptiblity 2) variant at 10q26 (A69S, rs10490924) has repeatedly been significantly associated with AMD. However, the physiological role of ARMS2 is still unclear. Similarly the deficiency of CFHR1 and CFHR3 proteins of the Factor H related protein family, influence the risk of AMD; in this case the deficiency is protective. The reason for this protective effect is still unclear. For this reason, the roles of ARMS2, CFHR1 and CFHR3 in AMD are elucidated in detail.

Complement is a central element of innate immune homeostasis in the human organisms. This cascade system is important to recognize and to efficiently attack infectious agents and, in addition, it also mediates the silent, non-inflammatory removal of modified autologous cells and cellular debris. A direct efficient activation of the complement cascade on the surface of infectious microbes is favorable and results in a damage and elimination of these foreign particles. At the same time, bystander host cells need maximum protection from the damaging effects of the activated system. Early in life, when the adaptive system is still evolving, the innate immune response is central for immune protection. Even slight changes in single components in form of mutations, polymorphisms, copy number variations or chromosomal rearrangements influence the balance of this central, evolutionary highly conserved immune defense network. Protective effects which are highly relevant early in life can develop to risk factors and predisposes for certain autoimmune disorders at a later age. Our work aims  at defining how single disease and infection associated gene polymorphisms affect infection, the immune evasion of pathogenic microbes and cause autoimmune disorders.