The Dept. of Immunology focuses on lymphatic and myeloid differentiation, immune regulation and inflammation. Chronic inflammation and autoimmune disease are leading causes of morbidity, psycho-siocal burden and economic loss in Western societies. In view of the central role of innate and adaptive immunity in these diseases, detailed insight into immune regulation is a requirement for elucidation of the immune pathogenesis of chronic inflammatory and autoimmune processes and the rational development of diagnostics and immune therapy.

The Postgraduate School Molecular Medicine has an extensive and active program in immune regulation and autoimmunity, consisting of a close collaboration between clinical and pre-clinical departments. Chronic inflammatory diseases of interest are type I diabetes, thyroiditis, affective disorders and schizophrenia (all having a major immuno-neuro-endocrine component), rheumatoid arthritis (RA) and the related disorder Sjögren’s disease, psoriasis, and the demyelinating diseases multiple sclerosis (MS) and Guillain-Barré syndrome (GBS).

The general premise is that the immune mechanisms driving the multi-factorial pathological processes in these different diseases of interest are highly analogous. Our overall aims within the frame of aforementioned diseases are to unravel:

• The immune (dys-)regulations in inflammatory capacity and antigen-presentation and the set point changes in monocytes, dendritic cells and macrophages underlying these diseases
• The numerical and functional abnormalities in T and B lymphocyte subsets underlying these diseases
• The influences of the neuro-endocrine system on leukocyte-target organ interaction
• The microbial and neuro-endocrine compounds driving the immune dys-regulations and the chronic inflammations
• The molecular mimicry and cross-reactivity for auto-antibody neurotoxicity
• The development of innovative animal models including conditional and cell type-specific transgenesis.

Research topics include basic immune pathogenic mechanisms (e.g. molecular mimicry in GBS and MS); immune-endocrine interactions (e.g. in the pathogenesis of postpartum thyroiditis and psychosis and in the linked amelioration of MS, thyroiditis and RA during pregnancy); molecular signaling pathways in chronic autoimmune inflammation (e.g. transcription factors in psoriasis and major psychiatric diseases, inflammatory gene signature expression in monocytes in major psychiatric and autoimmune diseases, epi-genetic regulation of these various genes); experimental immune therapy (e.g. antibodies against co-stimulatory molecules and cytokines); immune regulation by external factors (e.g. UV irradiation and skin inflammation, infection and MS activity); immune function and disease activity in MS; and immune dysregulation by aberrant development and activity of antigen presenting cells (e.g. in diabetes, Sjögren’s syndrome, thyroiditis, atherosclerosis, affective disorders, schizophrenia and histiocytosis).

Team

Close collaboration with clinical researchers who are well trained in immunology allows joint elaboration of scientifically relevant research questions, construction of well-characterized patient cohorts, and evaluation of experimental immune therapies. Specifically, the departments of Neurology (workgroup leaders Prof.Dr. R.Q. Hintzen, Dr. B.C. Jacobs, Prof.Dr. P.A. van Doorn), Dermatology (Prof.Dr. H.A.M. Neuman, Prof.Dr. E.P. Prens), Rheumatology (Prof.Dr. J.M.W. Hazes, Dr. E. Lubberts, Dr. R.J.E.M. Dolhain) and Internal Medicine (Dr. P.M. van Hagen) have integrated their immune research within this research line of the Molmed School.

There is additional close collaboration on the role of microbial compounds in immune regulation with the departments of Virology (Prof.Dr. A.D.M.E. Osterhaus), Medical Microbiology and Infectious Diseases (Prof.Dr. H.A. Verbrugh, Dr. H.P. Endtz, Prof.Dr. A. van Belkum). Furthermore, the departments of Internal Medicine (Prof.Dr. A.J. van der Lely, Prof.Dr. T.J. Visser) and Immunology collaborate on thyroid autoimmune disease and on diabetes, and the departments of Psychiatry (Prof.Dr. S. Kushner, Dr. V. Bergink, Dr. J.M. van Beveren) and Immunology on immune aberrancies in major affective disorders and schizophrenia. In addition, long-standing collaborations exist with the department of Genetics (Prof.Dr. J.H.J. Hoeymakers, Dr. J. Pothof) on UV-mediated effects on immunity and microRNA regulation of gene expression. Combining researchers with different backgrounds (e.g. the clinic, molecular biology, cellular immunology) working on these different diseases in a single integrated team significantly stimulates scientific discussion and output. The joint expertise allows coverage of a broad area of approaches and technology, ranging from patient cohort studies via functional in vitro and genetic analyses of patient material to several animal disease models in rodents and non-human primates including the generation of novel (conditional) transgene and knockout mouse models.

1. Distinct profiles of microRNAs were identified in different developmental stages of dendritic cells. Differentially expressed microRNAs were found to regulate M-CSF receptor expression, which appeared to be decisive in final maturation of these pivotal immune-regulating cells.
2. In addition to dendritic cell plasticity and multi-tasking the concept of division of labor between distinct dendritic cell subsets, e.g. in governing immunity versus tolerance, is gaining support. To unravel the relative importance of epidermal Langerhans cells versus dermal dendritic cells in the control of skin immunity and tolerance, we have developed a transgenic Langerhans cell depletion mouse model. Furthermore, we are applying dendritic cell-specific Cre/loxP-mediated gene targeting to better understand the molecular signals directing dendritic cell function
3. We idebtified abnormal local precursors for dendritic cells in the pancreas in a mouse model for type I diabetes.
4. Coherent partly overlapping, but distinct inflammatory transcriptomic fingerprints were detected in the monocytes of proportions of patients with bipolar disorder, schizophrenia, LADA, childhood onset type 1 diabetes, autoimmune thryroid disease and Sjögren’s disease reflecting previously found functional abnormalities in these cells; these fingerprints will be instrumental for the development of novel diagnostic and prognostic biomarker assays and for the identification of patients benefiting from a treatment targeting important fingerprint genes (COX-2, PDE4B, TNF, IFN-α)
5. We developed in vitro assays in which the role of ganglioside-like lipo-oligosaccharides of Campylobacter jejuni in the activation of human dendritic cells and B-cells was established.
6. We developed accurate and validated prognostic models based on early clinical and immunological characteristics to predict the IVIg treatment response and outcome in individual patients with the Guillain-Barré syndrome.  
7. B-cell clonality in cerebrospinal fluid of MS patients as an early event in the disease course was established.
8. The influence of pregnancy on T-lymphocyte function in MS and healthy individuals was established.
9. We found effects of novel MS and autoimmune risk genes on T-cell responses.
10. Using innovative EAE models and MS patient material in parallel, we demonstrated that phagocytic cells turned foam cell by excessive myelin uptake having anti-inflammatory function, that bacterial peptidoglycan is a cofactor in brain inflammation, and that lymph nodes draining myelin and axonal antigen from the brain contribute to disease relapse.

1. The further development within MOODINFLAME of monocyte, T cell and serum biomarker assays to diagnose and to identify individuals at risk to develop bipolar disorder, major mood disorders, post partum psychosis, schizophrenia, type 1 diabetes, autoimmune thyroid disease and Sjögren’s disease and the treatment of these patients/at risk individuals with new generation COX-2 inhibitors, PDE4B inhibitors, anti-oxidants, anti-TNF and anti IFN-receptor biologicals (personalized treatments)
2. Substantiate the mediators and pathways involved in the cross-reactive immune response to preceding infections that result in the Guillain-Barré syndrome.
3. Coordinate extensive international studies on disease modifiers and prediction of the treatment response and outcome in the Guillain-Barré syndrome, in collaboration with the International Neuropathy Consortium (INC) and Peripheral Nerve Society (PNS).
4. We will continue to apply conditional in vivo mutagenesis to better understand the role and molecular control of dendritic cells and monocytes/macrophages in immune regulation. Furthermore, we have recently made Langerhans cells accessible to this powerful approach by generating Langerhans cell-specific Cre mice. Functional analysis of these tg/KO mice will focus on relevant disease models of psoriasis (in cooperation with Prof.Dr. E.P. Prens, Dept. Dermatology), multiple sclerosis, rheumatoid arthritis (in cooperation with Dr. E. Lubberts, Dept. Rheumatology), allergic asthma (Prof.Dr. B.N.M. Lambrecht, Dr. R.W. Hendriks, Dept. Pulmonology) and colitis/IBD models (Dr. J.N. Samsom, Dept. Paedriatrics).
5. Animal EAE models will be further improved in both rodents and non-human primates to more faithfully mimick components of MS pathogenesis by applying conditional mutagenesis and alternative adjuvant strategies. Contributions of infectious pathogens as well as normal gut flora to MS/EAE susceptibility and disease course will be assessed. Tolerance control by glycosylation of brain components will be investigated.
6. To apply microRNA technology as an investigative, diagnostic and therapeutic tool to monitor and manipulate the developmental and activation state of myelomonocytic cells involved in various inflammatory conditions in patients and animal models of human disease. These include diabetes, psychiatric disease, histiocytosis, bacterial infection and atherosclerosis.

1.      Padmos RC, Schloot NC, Beyan H, Ruwhof C, Staal FJ, de Ridder D, Aanstoot HJ, Lam-Tse WK, de Wit H, de Herder C, Drexhage RC, Menart B, Leslie RD, Drexhage HA; LADA Consortium. Distinct monocyte gene-expression profiles in autoimmune diabetes. Diabetes 2008; 57:2768-73.

2.      Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de Ridder D, Kupka RW, Nolen WA, Drexhage HA. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry. 2008; 65:395-407.

3.      van Koningsveld R, Steyerberg EW, Hughes RAC, Swan AV, van Doorn PA, Jacobs BC. A clinical prognostic scoring system for Guillain-Barré syndrome. Lancet Neurol 2007;6:589-94.

4.      van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis and treatment of Guillain-Barré syndrome. Lancet Neurol 2008;7:939-50.

5.      Bennett CL and Clausen BE. Dendritic cell ablation in mice: promises, pitfalls and challenges. Trends Immunol. 2007; 28:519-25.

6.      Bennett CL, Noordegraaf M, Martina CA, Clausen BE. Langerhans cells are required for efficient presentation of topically applied hapten to T cells. J Immunol. 2007; 179:6830-5.

7.      Boven LA, van Meurs M, van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG, Aerts JM, Amor S, Nieuwenhuis EE, Laman JD. Myelin-laden macrophages are anti-inflammatory consistent with foam cells in multiple sclerosis. Brain 2006; 129:517-26.

8.      ‘t Hart BA, Hintzen RQ, Laman JD. Multiple sclerosis, a response-to-damage model. Trends Mol Med. 2009; 15:235-44.

9.      Hintzen RQ, Giovannoni G. CSF analysis in suspected MS: do bands aid? Neurology 2008; 70:1059-60.

10.  Neuteboom RF, Boon M, Catsman Berrevoets CE, Vles JS, Gooskens RH, Stroink H, Vermeulen RJ, Rotteveel JJ, Ketelslegers IA, Peeters E, Poll-The BT, De Rijk-Van Andel JF, Verrips A, Hintzen RQ. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 2008; 71:967-73.

11.  de Lau LM, de Vries JM, Kuipers E, van der Woude CJ, Kuipers EJ, Siepman DA, Sillevis Smitt PA, Hintzen RQ. Acute CNS white matter lesions in patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2009; 15:576-80.

12.  Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, Leenen PJM. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol. 2004; 172:4410-7.

13.  Cheng C, Tempel D, van Haperen R, de Boer HC, Segers D, Huisman M, van Zonneveld AJ, Leenen PJM, van der Steen A, Serruys PW, de Crom R, Krams R. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest. 2007; 117:616-26.

14.  Wildenberg ME, van Helden-Meeuwsen CG, van de Merwe JP, Drexhage HA, Versnel MA. Systemic increase in type I interferon activity in Sjögren's syndrome: a putative role for plasmacytoid dendritic cells. Eur J Immunol. 2008;38:2024-2033.