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1.
Transfer of monoclonal antibodies into breastmilk in neurologic and non-neurologic diseases.
LaHue, SC, Anderson, A, Krysko, KM, Rutatangwa, A, Dorsey, MJ, Hale, T, Mahadevan, U, Rogers, EE, Rosenstein, MG, Bove, R
Neurology(R) neuroimmunology & neuroinflammation. 2020;(4)
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Abstract
OBJECTIVE To review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases. METHODS We systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and "breastmilk," "breast milk," "breastfeeding," or "lactation." From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women. RESULTS Drug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections. CONCLUSIONS The current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.
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Exploring the Evidence for an Immunomodulatory Role of Vitamin D in Juvenile and Adult Rheumatic Disease.
Zou, J, Thornton, C, Chambers, ES, Rosser, EC, Ciurtin, C
Frontiers in immunology. 2020;:616483
Abstract
Vitamin D is synthesized in the skin following exposure to UVB radiation or is directly absorbed from the diet. Following hydroxylation in the liver and kidneys, vitamin D becomes its bioactive form, 1,25(OH)2D, which has been described to have potent immunomodulatory capacity. This review will focus on the effect of vitamin D in modulating the dysregulated immune system of autoimmune rheumatic diseases (ARD) patients across age, in particular in arthritis (rheumatoid arthritis and juvenile idiopathic arthritis), and systemic lupus erythematosus (with adult and juvenile onset). As well as delineating the impact of vitamin D on the innate and adaptive immune functions associated with each disease pathology, this review will also summarize and evaluate studies that link vitamin D status with disease prevalence, and supplementation studies that examine the potential benefits of vitamin D on disease outcomes. Exploring this evidence reveals that better designed randomized controlled studies are required to clarify the impact of vitamin D supplementation on ARD outcomes and general health. Considering the accessibility and affordability of vitamin D as a therapeutic option, there is a major unmet need for evidence-based treatment recommendations for the use of vitamin D in this patient population.
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Time to dissect the autoimmune etiology of cancer antibody immunotherapy.
Dougan, M, Pietropaolo, M
The Journal of clinical investigation. 2020;(1):51-61
Abstract
Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
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The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease.
Kiernan, K, MacIver, NJ
Frontiers in immunology. 2020;:622468
Abstract
Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly via the leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation.
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Vitamin D in autoimmune bullous disease.
Tukaj, S
Acta biochimica Polonica. 2020;(1):1-5
Abstract
Numerous epidemiological studies have suggested a link between vitamin D deficiency and the development of various autoimmune diseases, including diabetes mellitus type 1, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis or systemic lupus erythematosus. More recently, such a link has been also proposed for autoimmune bullous diseases (AIBD). This is a relatively rare and potentially life-threatening, organ-specific group of inflammatory skin diseases characterized by the presence of tissue-bound and circulating autoantibodies against various molecules present in desmosomes (in pemphigus diseases) or hemidesmosomes (in pemphigoid diseases). In addition to the well-known role of vitamin D in calcium and phosphate homeostasis, the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol), exerts potent effects on cellular differentiation and regulation of immune responses via binding to the vitamin D receptor present in most cells of the immune system. Since cells of both, the innate and adaptive immune systems, are known to be relevant in AIBD, the role of vitamin D analogues in the treatment of patients with these disorders deserves much attention. This mini-review summarizes recent epidemiological and experimental studies on vitamin D involvement in the autoimmune bullous diseases.
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Apoptosis in Autoimmunological Diseases, with Particular Consideration of Molecular Aspects of Psoriasis.
Krawczyk, A, Miśkiewicz, J, Strzelec, K, Wcisło-Dziadecka, D, Strzalka-Mrozik, B
Medical science monitor : international medical journal of experimental and clinical research. 2020;:e922035
Abstract
Apoptosis is a natural physiological process involving programmed cell death. Thanks to this process, it is possible to maintain the homeostasis of the body and the immune system. Dysfunctions of this mechanism lead to development of autoimmune diseases such as psoriasis; these diseases are chronic and treatment is extremely difficult. In psoriasis (a skin disease), apoptosis disorders are manifested by keratinocyte proliferation dysfunction. Autoimmune diseases coexisting with psoriasis include multiple sclerosis, autoimmune thyroid disease, and diabetes, but the common pathogenesis of these diseases is not fully understood. Given the heterogenous nature and chronic and recurrent course of psoriasis, the selection of an effective therapeutic strategy is still a problem. This literature review was focused on the process of apoptosis as a factor in the development of autoimmune diseases, with particular emphasis on psoriasis. The work also includes a review of therapeutic methods of psoriasis based on the latest literature.
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The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders.
Arts, RJW, Joosten, LAB, Netea, MG
Frontiers in immunology. 2018;:298
Abstract
During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.
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Pathogenesis, diagnosis and treatment of anaemia in immune-mediated gastrointestinal disorders.
Bergamaschi, G, Di Sabatino, A, Corazza, GR
British journal of haematology. 2018;(3):319-329
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Abstract
Immune-mediated disorders affecting the gastrointestinal (GI) tract may compromise GI integrity, interfere with the absorption of nutrients and cause bleeding and inflammation. All these features contribute to the pathogenesis of anaemia, the most prevalent extra-intestinal manifestation of immune-mediated GI disorders. Anaemia is most commonly due to iron deficiency and/or inflammation, but vitamin deficiencies and, more infrequently, autoimmune haemolysis or drug-induced myelosuppression can be involved. Here we address several issues related to the differential diagnosis and treatment of anaemia in immune-mediated GI disorders, giving particular relevance to the problem of iron deficiency anaemia associated with inflammation. It is emphasized how, in most cases, anaemias due to iron or vitamin deficiencies are best treated by parenteral administration of the deficient factor(s), and how the available high dose intravenous (IV) iron formulations can reduce ambulatory and social costs of IV iron supplementation, while improving patient's compliance to treatment. Actual and future treatment possibilities for anaemia of inflammation, involving the use of erythropoiesis stimulating agents, biologicals and hepcidin inhibitors are discussed.
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Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit?
Bizzaro, G, Antico, A, Fortunato, A, Bizzaro, N
The Israel Medical Association journal : IMAJ. 2017;(7):438-443
Abstract
Vitamin D deficiency is becoming an increasing problem worldwide. It should not be underestimated, not only due to the well-known consequences vitamin D deficiency has on bone health, but primarily because recent studies have shown how the biologically active form of vitamin D - 1,25(OH)2D - is involved in many biological processes, including immune system modulation. Moreover, the presence of a vitamin D receptor was discovered in almost all immune cells and some of its polymorphisms were found to be associated with increased incidence of autoimmune diseases. This finding led to a proposed link between vitamin D deficiency and autoimmune diseases. Patients affected by various autoimmune diseases showed low levels of vitamin D. However, it is not always clear whether vitamin D deficiency is the cause or rather a consequence of the disease. Limitations of the studies, such as the small number of patients, heterogeneity of selected groups, environmental conditions, methods used to measure vitamin D serum concentration and other confounding factors do not lead to unequivocal results to demonstrate a direct link between low vitamin D levels and autoimmune disease. Therefore, randomized trials are needed to clarify conflicting results.
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Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation.
Ettenger, R, Chin, H, Kesler, K, Bridges, N, Grimm, P, Reed, EF, Sarwal, M, Sibley, R, Tsai, E, Warshaw, B, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017;(6):1549-1562
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Abstract
The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.