Leukocyte adhesion deficiency Type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of β2 integrins. LAD-I is invariably associated with severe periodontal bone loss, historically attributed to lack of neutrophil surveillance of the periodontal infection. Here, we challenge this dogma by showing that the cytokine IL-17 plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients, or in LFA-1 (CD11a/CD18)-deficient mice that exhibit the LAD-I periodontal phenotype, was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue. The pathological elevation of IL-17 in the LFA-1–deficient periodontal tissue derived also from innate lymphoid cells. Strikingly, local treatment with anti-IL-17 (or anti-IL-23) in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Our findings therefore support an IL-17-targeted therapy for this condition.

Impaired wound healing states lead to substantial morbidity and cost with treatment resulting in an expenditure of billions of dollars per annum in the USA alone. Both chronic wounds and impaired acute wounds are characterized by excessive inflammation, enhanced proteolysis, and reduced matrix deposition. These confounding factors are exacerbated in the elderly, in part, as we report here, related to increased local and systemic tumor necrosis factor alpha(TNFα) levels. Moreover, we have used a secretory leukocyte protease inhibitor(SLPI) null mouse model of severely impaired wound healing and excessive inflammation, comparable to age-related delayed human healing, to demonstrate that topical application of anti-TNFα neutralizing antibodies blunts leukocyte recruitment and NFκB activation, alters the balance between M1 and M2 macrophages, and accelerates wound healing. Following antagonism of TNFα, matrix synthesis is enhanced, associated with suppression of both inflammatory parameters and NFκB binding activity. Our data suggest that inhibiting TNFα is a critical event in reversing the severely impaired healing response associated with the absence of SLPI, and may be applicable to prophylaxis and/or treatment of impaired wound healing states in humans.

Summary A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23–interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23–dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Polyreactive antibodies are a major component of the natural antibody repertoire and are capable of binding a variety of structurally unrelated antigens. Many of the properties attributed to natural antibodies, in fact, are turning out to be due to polyreactive antibodies. In humans, each day, billions of cells undergo apoptosis. In the present experiments, we show by ImageStream technology that although polyreactive antibodies do not bind to live T cells they bind to both the plasma membrane and cytoplasm of late apoptotic cells, fix complement, generate the anaphylatoxin C5a and increase by as much as 5 fold complement-mediated phagocytosis by macrophages. Of particular importance, T cells undergoing apoptosis following infection with HIV also bind polyreactive antibodies and are phagocytosed. We conclude that the polyreactive antibodies in the natural antibody repertoire contribute in a major way to the clearance of cells made apoptotic by a variety of natural and infectious processes.

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Background:Activation of type I and II interferon (IFN) pathways contributes to the pathogenesis of systemic autoimmune diseases. We have previously shown increased expression of the LINE-1 (L1) endogenous retrotransposon in systemic lupus erythematosus (SLE) kidneys and in minor salivary glands (MSG) from primary Sjögren’s syndrome patients (SS) that strongly correlates with IFNα expression in the same tissues. Moreover, an imbalance between type I and II IFNs in SS salivary gland tissues has been related to non-Hodgkin’s lymphoma (NHL) development. Members of a family of retroviral resistance factors (APOBECs) have been implicated in L1 control and are regulated by both type I and II IFNs.Objectives:We investigated whether these mechanisms are involved in the response to inappropriate expression of L1 retroelements in primary SS and SLE, as well as in SS related lymphomagenesis.Methods:MSG and kidney biopsy specimens were obtained from 41 patients with primary SS and 23 patients with SLE, respectively. Peripheral blood mononuclear cells (PBMC) and sera were also collected from 73 SLE patients. Relative mRNA expression was quantified by real-time polymerase chain reaction for full-length L1 transcripts, along with members of the APOBEC family [APOBEC3A, APOBEC3B, APOBEC3G, AID (activation-induced cytidine deaminase)] and IFNα and γ transcripts. Type I IFN activity was assessed in lupus plasma by a reporter cell assay. The induction of APOBEC3A and B by IFNα in healthy control PBMCs was also assessed.Results:APOBEC3A, previously implicated in control of endogenous retroelements, was increased in SS MSG and lupus nephritis kidney tissues and in SLE PBMC and strongly correlated with L1 retroelement expression in both SS and SLE tissues. APOBEC3A was also associated with IFNα mRNA expression in SS MSG tissues and lupus kidneys and with type I IFN activity in lupus plasma. While APOBEC3A expression was induced by IFNα, such a relationship was not observed with APOBEC3B. Moreover, a strong correlation was detected between AID and APOBEC3G with IFNγ expression in SS MSG tissue, a relationship particularly relevant to development of NHL.Conclusion:Increased expression of APOBEC3A reflects a host-intrinsic and IFNα-dependent mechanism regulating potentially harmful L1 retroelements in patients with SS and SLE. Moreover, IFNγ-related induction of APOBEC3G, together with AID, might contribute to SS-related lymphomagenesis by increasing mutational load or epigenetic alterations. These data reveal a previously unappreciated role of APOBEC family proteins in the pathogenesis of autoimmune disorders.Disclosure of Interests:None declared

The oral cavity is a unique stricture; it combines mucosal and bone tissue microenvironments with their respective immunological responses. In fact, oral mucosal inflammation leads to bone destruction in the prevalent human disease, periodontitis. In periodontitis, immune cells, in particular Th17 and neutrophil mediated responses have been linked to pathogenesis, however it is not yet understood how the stromal tissue microenvironment may participate in disease pathology. To date, studies in humans reveal inflammatory signatures in oral mucosal stromal cells of periodontitis, linked to neutrophil recruitment. To understand fibroblast responses and function in periodontitis, we performed scRNA-seq in mouse oral mucosa during a time course in the experimental periodontitis model. We characterize an early responding fibroblast subpopulation with a distinct inflammatory signature, characterized by induction of the IL33- ST2 cytokine axis. We confirm induction of soluble ST2 in oral mucosal fibroblasts during periodontitis and uncover an immune-regulatory role for ST2 within the oral microenvironment. Our work highlights the nature of oral mucosal immune-responsiveness and provides insights into a common human disease. Supported by NIH intramural funding