Gender incongruence of adolescence and adulthood: acceptability and clinical utility of the World Health Organization’s proposed ICD-11 criteria

The World Health Organization (WHO) is currently updating the tenth version of their diagnostic tool, the International Classification of Diseases (ICD, WHO, 1992). Changes have been proposed for the diagnosis of Transsexualism (ICD-10) with regard to terminology, placement and content. The aim of this study was to gather the opinions of transgender individuals (and their relatives/partners) and clinicians in the Netherlands, Flanders (Belgium) and the United Kingdom regarding the proposed changes and the clinical applicability and utility of the ICD-11 criteria of ‘Gender Incongruence of Adolescence and Adulthood’ (GIAA). A total of 628 participants were included in the study: 284 from the Netherlands (45.2%), 8 from Flanders (Belgium) (1.3%), and 336 (53.5%) from the UK. Most participants were transgender people (or their partners/relatives) (n = 522), 89 participants were healthcare providers (HCPs) and 17 were both healthcare providers and (partners/relatives of) transgender people. Participants completed an online survey developed for this study. Most participants were in favor of the proposed diagnostic term of ‘Gender Incongruence’ and thought that this was an improvement on the ICD-10 diagnostic term of ‘Transsexualism’. Placement in a separate chapter dealing with Sexual- and Gender-related Health or as a Z-code was preferred by many and only a small number of participants stated that this diagnosis should be excluded from the ICD-11. In the UK, most transgender participants thought there should be a diagnosis related to being trans. However, if it were to be removed from the chapter on “psychiatric disorders”, many transgender respondents indicated that they would prefer it to be removed from the ICD in its entirety. There were no large differences between the responses of the transgender participants (or their partners and relatives) and HCPs. HCPs were generally positive about the GIAA diagnosis; most thought the diagnosis was clearly defined and easy to use in their practice or work. The duration of gender incongruence (several months) was seen by many as too short and required a clearer definition. If the new diagnostic term of GIAA is retained, it should not be stigmatizing to individuals. Moving this diagnosis away from the mental and behavioral chapter was generally supported. Access to healthcare was one area where retaining a diagnosis seemed to be of benefit

Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells

In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs)) by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors), the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC). This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9) or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7). Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response

Standards of Care for the Health of Transsexual, Transgender and Gender Nonconforming People

The World Professional Association for Transgender Health promotes the highest standards of health care for individuals through the articulation of Standards of Care (SOC) for the Health of Transsexual, Transgender, and Gender Nonconforming People. The SOC are based on the best available science and expert professional consensus. The overall goal of the SOC is to provide clinical guidance for health professionals to assist transsexual, transgender, and gender nonconforming people with safe and effective pathways to achieving lasting personal comfort with their gendered selves, in order to maximize their overall health, psychological well-being, and self-fulfillment. This assistance may include primary care, gynecologic and urologic care, reproductive options, voice and communication therapy, mental health services (e.g., assessment, counseling, psychotherapy), and hormonal and surgical treatments. While this is primarily a document for health professionals, the SOC may also be used by individuals, their families, and social institutions to understand how they can assist with promoting optimal health for members of this diverse population. This is the 7th version of the Standards of Care since the original 1979 document. The first six versions were published in 1979, 1980, 1981, 1990, 1998, and 2001. Version 7 of the Standards of Care (SOC) for the Health of Transsexual, Transgender, and Gender Nonconforming People will be available in several additional places for wide distribution and ease of access

BAFF Mediates Splenic B Cell Response and Antibody Production in Experimental Chagas Disease

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Central and South America. It affects 20 million people and about 100 million people are at risk of infection in endemic areas. Some cases have been identified in non-endemic countries as a consequence of blood transfusion and organ transplantation. Chagas disease presents three stages of infection. The acute phase appears one to two weeks after infection and includes fever, swelling around the bite site, enlarged lymph glands and spleen, and fatigue. This stage is characterized by circulating parasites and many immunological disturbances including a massive B cell response. In general, the acute episode self-resolves in about 2 months and is followed by a clinically silent indeterminate phase characterized by absence of circulating parasites. In about one-third of the cases, the indeterminate phase evolves into a chronic phase with clinically defined cardiac or digestive disturbances. Current knowledge suggests that the persistence of parasites coupled with an unbalanced immune response sustain inflammatory response in the chronic stage. We believe that an effective treatment for chronic Chagas disease should combine antiparasitic drugs with immunomodulators aimed at reducing inflammation and autoreactive response. Our findings enlighten a new role of BAFF-BAFF-R signaling in parasite infection that partially controls polyclonal B cell response but not parasitespecific class-switched primary effectors B cells

B Cell Activating Factor (BAFF) and T Cells Cooperate to Breach B Cell Tolerance in Lupus-Prone New Zealand Black (NZB) Mice

The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help

Lipid Motif of a Bacterial Antigen Mediates Immune Responses via TLR2 Signaling

The cross-talk between the innate and the adaptive immune system is facilitated by the initial interaction of antigen with dendritic cells. As DCs express a large array of TLRs, evidence has accumulated that engagement of these molecules contributes to the activation of adaptive immunity. We have evaluated the immunostimulatory role of the highly-conserved outer membrane lipoprotein P6 from non-typeable Haemophilus influenzae (NTHI) to determine whether the presence of the lipid motif plays a critical role on its immunogenicity. We undertook a systematic analysis of the role that the lipid motif plays in the activation of DCs and the subsequent stimulation of antigen-specific T and B cells. To facilitate our studies, recombinant P6 protein that lacked the lipid motif was generated. Mice immunized with non-lipidated rP6 were unable to elicit high titers of anti-P6 Ig. Expression of the lipid motif on P6 was also required for proliferation and cytokine secretion by antigen-specific T cells. Upregulation of T cell costimulatory molecules was abrogated in DCs exposed to non-lipidated rP6 and in TLR2−/− DCs exposed to native P6, thereby resulting in diminished adaptive immune responses. Absence of either the lipid motif on the antigen or TLR2 expression resulted in diminished cytokine production from stimulated DCs. Collectively; our data suggest that the lipid motif of the lipoprotein antigen is essential for triggering TLR2 signaling and effective stimulation of APCs. Our studies establish the pivotal role of a bacterial lipid motif on activating both innate and adaptive immune responses to an otherwise poorly immunogenic protein antigen

Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person

Intersexuality and Trans-Identities within the Diversity Management Discourse

Within both the scientific discourse on workforce diversity, and diversity management practice, intersexuality and transgender issues have hitherto remained marginalized topics. This chapter gives an overview of the discourses on both phenomena, and proposes starting points for more inclusive organizational diversity management initiatives. It is shown that both topics represent different aspects of the category of "gender". The common practice of conceptually lumping together intersexuality, transgenderism, and sexual orientation can be seen as one important reason that intersexuality and transgenderism are rarely considered in organizational diversity management programs in terms of concrete action. Against this background, a modified, and more integrated approach to structuring the workforce alongside the different dimensions of diversity is proposed. It is shown that the categories of "biological sex and gender", "gender identity", and "sexual orientation" cannot be regarded as being separate from each other. They represent, rather, an interrelated organizational field of action that should be considered as being one interrelated topic for organizational diversity practices. This chapter derives this claim theoretically and discusses the consequences for organizational diversity management practices. For most organizations, this would mean a fundamental rethinking of their goals, in terms of workforce diversity, and the shaping of their diversity management programs

Cytoskeletal control of B cell responses to antigens.

The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton is extensively coupled to B cell receptor (BCR) signalling pathways, and defects of the actin cytoskeleton can either promote or suppress B cell activation. Recent insights from studies using single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also have a role in the adaptation of B cell subsets to specialized tasks during antibody responses