Borrelia and Autoimmune Diabetes

[LymeEnigma]

Association of CD4+ CD25+ T Cells with Prevention of Severe Destructive Arthritis in Borrelia burgdorferi-Vaccinated and Challenged Gamma Interferon-Deficient Mice Treated with Anti-Interleukin-17 Antibody

Dean T. Nardelli,1,2 Matthew A. Burchill,1,2 Douglas M. England,3,4 Jose Torrealba,4,5 Steven M. Callister,6 and Ronald F. Schell1,2,7*

Wisconsin State Laboratory of Hygiene,1 Departments of Bacteriology,2 Medical Microbiology and Immunology,7 Pathology and Laboratory Medicine,4 Surgery, University of Wisconsin,5 Department of Pathology, Meriter Hospital, Madison,3 Microbiology Research Laboratory and Department of Infectious Diseases, Gundersen Lutheran Medical Center, La Crosse, Wisconsin6

Received 14 May 2004/ Returned for modification 13 July 2004/ Accepted 22 July 2004


ABSTRACT

CD4+ CD25+ T cells are a population of regulatory T cells responsible for active suppression of autoimmunity. Specifically, CD4+ CD25+ T cells have been shown to prevent insulin-dependent diabetes mellitus, inflammatory bowel disease, and pancreatitis. Here, we present evidence that CD4+ CD25+ T cells also play a major role in controlling the severity of arthritis detected in Borrelia burgdorferi-vaccinated gamma interferon-deficient (IFN-{gamma}°) C57BL/6 mice challenged with the Lyme spirochete. When B. burgdorferi-vaccinated and challenged IFN-{gamma}° mice were treated with anti-interleukin-17 (IL-17) antibody, the number of CD4+ CD25+ T cells increased in the local lymph nodes. Furthermore, histopathologic examination showed the mice to be free of destructive arthritis. When these anti-IL-17-treated B. burgdorferi-vaccinated and challenged mice were also administered anti-CD25 antibody, the number of CD4+ CD25+ T cells in the local lymph nodes decreased. More importantly, severe destructive arthropathy was induced. In addition, delayed administration of anti-CD25 antibody decreased the severity of the arthritis. These results suggest that CD4+ CD25+ T cells are involved in regulation of a severe destructive arthritis induced with an experimental model of vaccination and challenge with B. burgdorferi.

Full article (free): cvi.asm.org/cgi/content/full/11/6/1075

*edited to clarify header.

[LymeEnigma]

Modulation of Murine Lyme Borreliosis by Interruption of the B7/CD28 T-Cell Costimulatory Pathway

Marie-Claude Shanafelt,1* Insoo Kang,1 Stephen W. Barthold,2 and Linda K. Bockenstedt1*
Department of Internal Medicine1 and Section of Comparative Medicine,2 Yale University School of Medicine, New Haven, Connecticut 06520

*Corresponding author. Mailing address: 610 LCI, Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8031. Phone: [phone]. Fax: [phone]. E-mail: [e-mail].
Editor: R. E. McCallum

Received May 29, 1997; Revisions requested August 13, 1997; Accepted October 20, 1997.


Abstract
Recent studies have implicated cytokines associated with Th2 cells in the genetic resistance to murine Lyme borreliosis. Because the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th-cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to the Th2 cytokine profile and development of arthritis in BALB/c mice infected with Borrelia burgdorferi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin 4 (IL-4) and upregulation of gamma interferon (IFN-γ) responses by B. burgdorferi-specific T cells and by reduction of B. burgdorferi-specific immunoglobulin G. Despite the shift toward a Th1 cytokine pattern, which others have associated with disease susceptibility, the severity of arthritis was unchanged. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies or CTLA-4Ig enhanced IFN-γ production over that seen with CD86 blockade alone, yet augmentation of this Th1-associated cytokine did not enhance disease. These results demonstrate that IL-4 production by T cells in B. burgdorferi-infected BALB/c mice is dependent upon CD86/CD28 interaction and that this cytokine does not contribute significantly to host resistance to the development of arthritis. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-γ-producing T cells in B. burgdorferi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. These studies may provide insight into the role of the B7/CD28 pathway in other infectious and autoimmune diseases in which deviation of Th cell immune responses occurs and antigen is persistently present.

Lyme disease is a multisystem illness due to infection with the tick-transmitted spirochete Borrelia burgdorferi. Experimental infection of laboratory mice with B. burgdorferi results in acute arthritis and carditis that reproducibly peak at 2 to 4 weeks of infection and then resolve within 3 months despite spirochete persistence (4). Studies using SCID mice, which lack functional T and B cells, have demonstrated that disease is due to the innate immunity of the host and can occur in the absence of specific immune responses (6, 28). The persistent and progressive nature of disease manifestations in SCID mice underscores the importance of T and B cells in initiating disease regression (5, 6, 28). Recent studies support the additional role of specific immunity in modulating disease severity via direct effects on spirochete burden through B. burgdorferi-specific antibodies (5) and indirectly through Th cell-associated cytokines that influence the activation of innate immune cells (14, 23). In particular, the dominance of Th1-type responses, which support macrophage activation, in patients with chronic Lyme arthritis has implicated this T-cell phenotype in the development and perpetuation of severe inflammatory disease (32, 37). Th1-type responses have also been observed during B. burgdorferi infection of C3H mice, a disease-susceptible strain, whereas Th2 responses, which promote B-cell functions, can be detected in BALB/c mice, a comparatively disease-resistant strain (14, 23). Despite the greater inflammatory response in C3H mice, their pathogen burden as assessed by quantitative PCR of spirochete DNA remains higher than that of disease-resistant mouse strains (36), suggesting that the recruitment of innate immune cells is appropriate yet ineffective at controlling infection (29).

In addition to signals provided by T-cell antigen receptor engagement, the interaction of costimulatory molecules present on antigen-presenting cells (APCs) with their ligands on T cells is believed to be necessary for the initial priming of naive T cells. In particular, the B7/CD28 costimulatory pathway has been implicated in the differentiation of naive Th0 cells into Th1 and Th2 subsets (33). The mechanisms by which these molecules assist in the priming of the T-cell immune response are complex and poorly understood. Two members of the B7 family have been characterized, CD80 and CD86 (also known as B7-1 and B7-2, respectively), and differ not only in their binding properties to CD28 on T cells but also in the timing of their appearance on conventional APCs during the initiation of an immune response (11). CD86 appears earlier on the surface of mitogen-activated APCs and has a lower affinity for CD28 than does CD80. Once activated, T cells express CTLA-4, a second receptor to which both CD80 and CD86 bind with greater affinity than they bind CD28 (21). Interaction of CD80/CD86 with CTLA-4 can downregulate the T-cell immune response (35). Blockade of CD86 during the initiation of a T-cell response results in an immune response oriented toward a Th1 phenotype, whereas a similar blockade of CD80 does not consistently favor a Th2 phenotype (20). Experiments using mutant mice deficient in CD80 and/or CD86 reveal the important role of these molecules in sustaining a Th-cell phenotype and, in the case of CD86 expression, in the development of a Th2 response (20). Costimulation through the B7/CD28 pathway contributes to the expansion of autoimmune disease processes seen in experimental autoimmune encephalitis (17, 27), a predominantly Th1-associated disease, and autoimmune diabetes (19). Studies using a soluble recombinant form of CTLA-4 designated CTLA-4Ig have supported many of the observations made with anti-B7 antibodies (13, 19, 26).

We have recently reported that the Th2 response of B. burgdorferi-infected BALB/c mice is preceded by a Th1 response and that the presence of interleukin 4 (IL-4) is associated with accelerated resolution of arthritis (12). A hind-foot inoculation route was used in that study so that T-cell responses could be examined in lymph nodes adjacent to joints afflicted with arthritis. We demonstrated that this route of inoculation induces moderately severe arthritis in BALB/c mice at day 14 of infection that undergoes more rapid regression than the arthritis seen in similarly infected C3H mice, in which IL-4 responses are not detectable. Previous studies have shown that treatment of mice with anti-IL-4 monoclonal antibody (MAb) exacerbates arthritis in BALB/c mice assessed at intervals corresponding to the plateau and resolution phases of disease, providing evidence that IL-4 modulates the severity of established arthritis (14, 23). The influence of Th2 cell effector functions on the development of arthritis remains unknown. In the current study, we have examined the effects of interruption of Th2 cell differentiation by B7/CD28 blockade with anti-CD80 and/or anti-CD86 MAb or CTLA-4Ig on the cytokine profiles and development of arthritis in BALB/c mice infected with B. burgdorferi.

Full article (free): www.pubmedcentral.nih.gov/articlerender.fcgi?artid=107886

*edited to clarify header.

[LymeEnigma]

Autoimmune type 1 diabetes: resolved and unresolved issues

Abner Louis Notkins1 and Åke Lernmark2

1Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA
2Department of Medicine, Robert H. Williams Laboratory, University of Washington, Seattle, Washington, USA

Address correspondence to: Abner L. Notkins, National Institutes of Health, Building 30, Room 121, 30 Convent Drive, MSC 4322, Bethesda, Maryland 20892-4322, USA. Phone: [phone]; Fax: [phone]; E-mail: [e-mail].

Type 1 diabetes, also known as either juvenile diabetes (because of the early age of onset) or insulin-dependent diabetes mellitus (because of the clinical need for insulin), is now widely thought to be an organ-specific autoimmune disease. Here we wish to summarize some generally accepted facts about this disease and then give our perspectives on unresolved issues surrounding prediction, pathogenesis, and treatment. In particular, we will discuss markers of the disease, such as autoantibodies against pancreatic islet cell antigens.

Full article (free): www.jci.org/articles/view/14257

[LymeEnigma]

Histopathology. 2008 Jun;52(7):877-84. Epub 2008 May 6.

Detection of spirochaetal microorganisms by focus floating microscopy in necrobiosis lipoidica in patients from central Europe.

Eisendle K, Baltaci M, Kutzner H, Zelger B.

Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, Austria. [e-mail]

AIMS: Necrobiosis lipoidica (NL) is a chronic inflammatory skin disease with unknown aetiology. The aim was to determine the presence of spirochaetal microorganisms in NL. METHODS AND RESULTS: Focus-floating microscopy (FFM) is a modified immunohistochemical technique that was developed to detect borrelial spirochaetes within tissue sections. It has proven to be more sensitive for the detection of spirochaetes than polymerase chain reaction (PCR). Fifty-six cases of NL as well as 44 negative and 33 positive controls were investigated for the presence of Borrelia within tissue specimens. Using FFM, Borrelia could be detected in 42 cases (75.0%) and were seen significantly more often in histologically active inflammatory-rich (38/41, 92.7%) than in inflammatory-poor (4/15, 26.7%) cases of NL (P < 0.001). Seven cases investigated with a Borrelia-specific PCR (23s-RNA) remained negative. In contrast, FFM was positive in 30 of 33 (90.9%) positive controls of acrodermatitis chronica atrophicans and 15 of the positive controls (45.5%) were also positive with PCR, whereas no negative controls revealed any microorganisms. CONCLUSIONS: Detection of spirochaetes in NL points to a specific involvement of B. burgdorferi or other similar strains in the development of or trigger for this disease.

PMID: 18462358 [PubMed - indexed for MEDLINE
www.ncbi.nlm.nih.gov/pubmed/18462358