Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation

Integrin-mediated interactions between hematopoietic cells and their microenvironment are important for the development and function of immune cells. Here, the role of the integrin adaptor Kindlin-3 in B cell homeostasis is studied. Comparing the individual steps of B cell development in B cell-specific Kindlin-3 or alpha4 integrin knockout mice, we found in both conditions a phenotype of reduced late immature, mature, and recirculating B cells in the bone marrow. In the spleen, constitutive B cell-specific Kindlin-3 knockout caused a loss of marginal zone B cells and an unexpected expansion of follicular B cells. Alpha4 integrin deficiency did not induce this phenotype. In Kindlin-3 knockout B cells VLA-4 as well as LFA-1-mediated adhesion was abrogated, and short-term homing of these cells in vivo was redirected to the spleen. Upon inducible Kindlin-3 knockout, marginal zone B cells were lost due to defective retention within 2 weeks, while follicular B cell numbers were unaltered. Kindlin-3 deficient follicular B cells displayed higher IgD, CD40, CD44, CXCR5, and EBI2 levels, and elevated PI3K signaling upon CXCR5 stimulation. They also showed transcriptional signatures of spontaneous follicular B cell activation. This activation manifested in scattered germinal centers in situ, early plasmablasts differentiation, and signs of IgG class switch

Anchor Side Chains of Short Peptide Fragments Trigger Ligand-Exchange of Class II MHC Molecules

Class II MHC molecules display peptides on the cell surface for the surveillance by CD4+ T cells. To ensure that these ligands accurately reflect the content of the intracellular MHC loading compartment, a complex processing pathway has evolved that delivers only stable peptide/MHC complexes to the surface. As additional safeguard, MHC molecules quickly acquire a ‘non-receptive’ state once they have lost their ligand. Here we show now that amino acid side chains of short peptides can bypass these safety mechanisms by triggering the reversible ligand-exchange. The catalytic activity of dipeptides such as Tyr-Arg was stereo-specific and could be enhanced by modifications addressing the conserved H-bond network near the P1 pocket of the MHC molecule. It affected both antigen-loading and ligand-release and strictly correlated with reported anchor preferences of P1, the specific target site for the catalytic side chain of the dipeptide. The effect was evident also in CD4+ T cell assays, where the allele-selective influence of the dipeptides translated into increased sensitivities of the antigen-specific immune response. Molecular dynamic calculations support the hypothesis that occupation of P1 prevents the ‘closure’ of the empty peptide binding site into the non-receptive state. During antigen-processing and -presentation P1 may therefore function as important “sensor” for peptide-load. While it regulates maturation and trafficking of the complex, on the cell surface, short protein fragments present in blood or lymph could utilize this mechanism to alter the ligand composition on antigen presenting cells in a catalytic way

A call for further action in reply to Rose and colleagues (2020)

Rose and colleagues are prominent scholars who have brought insights from across the social and health sciences to promote a compelling case for significant action to address inequalities in both physical and mental health. Below, we offer further points of support, critique and clarification in the spirit of co-operation, which appears to be central to the agenda of Rose and colleagues. The open letter is particularly useful in drawing renewed attention to how necessary it is to remind decision-makers of the need for structural changes to ensure equity in health for all. Many of the key arguments posed in the letter have also been evident in emergency management and community psychology literatures for some time. These literatures document how adverse socio-economic conditions often worsen outcomes from natural and person-centered disasters, particularly for people who already endure vulnerabilities (Luna, 2009; Tierney, 2019; Wisner et al., 2004; Blake et al., 2017)1-4. As is the case with other disasters, socio-political situatedness in terms of poverty, insecure work, discrimination and marginalization, and poor housing are influencing peoples’ psychological, physical, cultural and spiritual reactions to COVID-19. Therefore, it is vital to contest the unjust, social structures that perpetuate and exaggerate such adverse conditions, and champion for fairer and just solutions. We can do so by drawing on existing resources, such as the Sendai framework that offer responses to inequalities in outcomes following disasters. Such frameworks offer pathways of action to address urgent and critical responses to protect livelihoods, health and ecosystems for everyone (United Nations, 2015)5. We agree that many of the well-publicized predictions of a ‘tsunami’ of mental health concerns stemming from the present pandemic may well be overstated. Rose and colleagues rightfully assert that, regardless, it is important to address issues around resourcing and community development, and to stretch our collective efforts towards socio-economic transformations. It is also necessary to note that, due to ongoing inequities and a lack of adequate response to the consequences of everyday injustices (poverty and discrimination), mental illness is already endemic in many countries. Systems of response also need to be re-designed to address the inverse care law (Hart, 1971)6 whereby people who need care the least consume the most. Conversely, people who need care the most, access the least. Increases in service access proposed by Rose and colleagues are urgent. It is important to put initiatives in place to help people in distress to cope by enhancing early intervention and peer-support systems. Training more mental health professionals to meet the existing complex needs of diverse communities is crucially important. Our concern with an emphasis on therapeutic training and interventions that predominantly target individuals in distress is not to question its effectiveness in addressing certain difficulties such as trauma, anxiety and low mood. Nor is the only challenge the limited reach (i.e., the number of people that can be assisted) of this strategy and issues of scalability. Our concern relates to how such responses are predominately ameliorative, rather than preventative in orientation. Responses to wide-scale human suffering that only focus on therapeutic interventions should be treated with suspicion as often conservative, bureaucratic, and as a failure of political imagination. The fixation on therapeutic responses can act as an ‘action distraction’, which contributes to a fixation on responses to reduce suffering within individuals. This can result in the pacification and obscuring of calls for wider reaching efforts to promote community level wellness, and to prevent mental ill-health through preventive macro structural changes. To address health inequities and differentials across persons and population groups, we must also address the structural inequities that drive ill-health. We need to look further ‘upstream’ and prevent people from becoming ill (Hodgetts & Stolte, 2017)7. Increased access to therapeutic interventions needs to be positioned overtly as part of larger strategies towards systemic change. We applaud Rose and colleagues for also raising the need for a broader change agenda. As Rose and colleagues also propose, redistributive policies and practices are important in addressing issues of inequity and health inequalities. In doing so, these authors adopt a well-worn population health position that is enshrined in many nation states within graduated taxation and cash transfer systems. We would add that, the levels of inequity that many communities now face, despite the existence of such redistributive initiatives, suggests the need to consider other more radical strategies for change. After all, it is in historical moments like the present that it becomes more possible to seize the initiative and to consider rebooting the whole socio-economic system (neoliberalism), which is driving inequities in life chances and health. In this context, increases in redistributive policies can be re-imagined as ‘stopgap measures’ that are useful whilst we formulate more sustainable and transformative systems for ensuring equity, social justice and health for all. This requires us to ask if, for example, now is the time for jubilee? Is now the time to introduce policies such as universal basic incomes, maximum wage settings, and resource co-ownership models? Should the ancient concept of the commons (shared resources that are available to humanity) be embraced as a central principle for a more just economic system (Standing, 2019)8? What we are signaling here is the need to be even bolder and to broaden the conversation regarding how to relieve people from debt servitude and ensure nobody has to subject themselves to often abusive and dehumanizing penal welfare and social service systems (Hodgetts & Stolte, 2017)7. Such structural transformations may actually reduce the need for therapists and such expensive service systems. We should be asking more questions to which we do not have perfect answers. One avenue for addressing discrimination in the health, penal welfare and social services nexus in many nation states is to disassemble these systems and to provide the resources they consume directly to people in need. If people are resourced to govern their own affairs collectively, the chances of their flourishing alongside others are increased. This line of reasoning speaks to issues of self-determination and is a feature of calls from indigenous groups, in particular, to (re)gain guardianship over the resources that have been taken from them. Additionally, in addressing issues of inequality and discrimination in present systems, it is important to not limit our historical gaze. For example, Rose and colleagues assert that economic supports have been stripped away over the last decade. We agree, and would also foreground the impacts of longer time scales of dispossession and inequality that have set the stage for injustices in many nation states today. The present crises in many countries have been shaped by Neoliberalism over the past 40 years. These crises are also the products of historical processes of colonization/imperialism that continue to negatively impact minoritized communities. Relatedly, responses called for by Rose and colleagues will need to be reformulated in context specific ways. What is appropriate for the United Kingdom in addressing issues of diversity may not necessarily be appropriate in contexts such as Aotearoa New Zealand. In our context, the English version of the Treaty of Waitangi [1] (signed in 1840 by the British Crown and Māori leaders) set the stage for the dispossession of land, resources, power and cultural practices from Māori. Subsequent exploitation by the Crown has resulted in ongoing structural inequities. As such, systemic changes will need to include the enactment of genuine Treaty of Waitangi principles that are not exploitative and extractive. This could mean that, for example, iwi (tribes) exercise guardianship over the provision of health, social and education services for their members, and for other people residing within their tribal boundaries. This would likely result in a refocusing of initiatives away from short-term economic returns and towards a longer-term, inclusive and equitable strategic focus. For instance, Māori often operate from the position of intergenerational planning, capacities and relationships whereby certain decision-making roles are assigned to kaumatua (elders) as wisdom holders, alongside often middle aged "executive leaders" (enactors) who are supported by rangatahi (youth), and inspired by pēpi (infants). More broadly, such transformations are about honouring localised treaties and embracing indigenous rights and knowledges through enactments of generational change strategies designed to achieve healthy futures for all. We are surprised that the open letter appears to take on a somewhat executive tone and does not feature the language of collaboration as much as we feel is warranted. From our perspective, achieving effective change requires us to look out beyond our own expertise, models and journals. Recognising the socio-political situatedness of people’s lives and who gets to have a voice in decision-making processes is particularly crucial during and after disasters. Rasche (2018)9 reminds us that the social location and expertise of speakers often brings about possibilities to become an authority on other peoples’ situations. It is important that we engage directly with people who are adversely affected by the structures and issues to which we are trying to find effect responses. Policies and systems that are co-designed with the people being targeted tend to be more effective. To work effectively with others, it is also important we decentre our own ‘expert’ voices in order to hear the voices of others who have gained phronetic wisdom from having to carry the weight of adversity. Part of our shared change agenda must be to address inequities regarding who gets to be central to conversations and initiatives for change, and whose knowledge is valued and heard in these processes. We cannot leave the formulation and implementation of change strategies to the usual suspects. We are sure Rose and colleagues would agree that there are considerable sensitivities in considering efforts to work in partnership across dominant and marginalized communities. In the process, it is important to avoid falling into the trap of using labels that collapse diverse communities together as the ‘others’ (Fakim & Macaulay, 2020)10. For example, the BAME acronym used by Rose and colleagues is considered highly problematic by many members of the diverse groups that are supposedly ‘encapsulated’ in this term. For many, BAME is a distancing, cold and administrative ‘white term’. It homogenises and simplifies the heterogeneity of the intertwined histories of adversity that are experienced in varying ways by diverse groups of people. Such terms also act as apolitical euphemisms for historically politicised and reclaimed notions, such as Black, queer and indigenous. A key message in our response is that what we need to advocate collectively is not only more equitable access to mental health and community services, but also access to justice, sustainable incomes, adequate housing, good food, and supportive and violence-free relationships. As Rose and colleagues note, we need to ‘build back better’. This requires us to unpack whose notion of ‘better’ is being advocated. Who gets to decide what we mean by the creation of societies that are more equitable and offer fairer access to resources, so as those necessary to promote and sustain human flourishing. We were surprised that in asserting the need to build back better, Rose and colleagues did not refer to existing global structures that offer avenues for negotiating and enacting shared visions for humanity and wellness. There is an opportunity to link our efforts in with the 17 interwoven United Nations Sustainable Development Goals (SDGs). Widely consulted and signed-up to by stakeholder groups from almost 200 United Nations, the SDGs have been in effect since 2016 and will run till 2030. Directly relevant to our present dialogue, psychologists specifically fought to have mental health included in this global development agenda, under SDG-3. Of the remaining 16 SDGs, particularly important are SDG-17 (Partnerships for development whereby those targeted are positioned centrally in the formulation, design and implementation of change processes) and SDG-8 (Decent Work for all, which includes access to Sustainable Livelihoods and Wellbeing at Work). In advocating for change it is important to avoid re-inventing the wheel. As imperfect as they are, the 17 SDGs offer a platform for change on a global scale and in ways that preserve our geographical specificities. The wider point of these goals, and other structures like the Global Compact and the Sendai Framework, is that they offer accountability structures that can help determine the distribution of resources and opportunities for action within and across nation states. These initiatives can be harnessed to help us redress structural inequities, injustices, exclusions and violations of Human Rights. We would like to thank Wellcome Open Research for providing this opportunity to respond to the seminal open letter by Rose and colleagues

Relational ethics meets principled practice in community research engagements to understand and address homelessness

Growing homelessness in Aotearoa New Zealand stems primarily from rising inequalities and poverty. Drawing from scholarship on relational ethics, principled practice and Māori cultural concepts, this paper offers our reflections on nearly two decades of collective work to document and address homelessness. Central to the approach outlined are enduring community partnerships, the cultivation of reciprocal relations, and time spent with homeless people and those trying to work with them. We present exemplars for how we draw on everyday interactions with homeless people and agency staff to enhance local service and broader systemic responses to homelessness

Stakeholders under Pressure: corporate governance and labour management in Germany and Japan

A small but significant stream of research has emerged on how changes in corporate governance impact labour management, particularly in countries with stakeholder-oriented corporate governance. This paper briefly reviews existing empirical and theoretical literature on the links between corporate governance and labour management. Then it compares recent trends in Germany and Japan in terms of how changes in corporate governance affect the distribution of value-added, employment adjustment, pay systems and employee participation. Germany and Japan have proven able to adapt and modify their stakeholder model of employment and employee participation to changing circumstances. However, the size of the core model is getting smaller. Copyright Blackwell Publishing Ltd 2005.

Vertical Disintegration and the Disorganization of German Industrial Relations-super-1

Drawing on case studies from the telecommunications and auto industries, the authors argue that the vertical disintegration of major German employers is contributing to the disorganization of Germany's dual system of in-plant and sectoral negotiations. Subcontractors, subsidiaries and temporary agencies often have no collective bargaining institutions or are covered by different firm-level and sectoral agreements. As core employers move jobs to these firms, they introduce new organizational boundaries across the production chain and disrupt traditional bargaining structures. Worker representatives are developing new campaign approaches and using residual power at large firms to establish representation in new firms and sectors, but these have not been successful at rebuilding co-ordinated bargaining. Copyright Blackwell Publishing Ltd/London School of Economics 2007.

Vertical disintegration and the disorganization of German industrial relations

Drawing on case studies from the telecommunications and auto industries, the authors argue that the vertical disintegration of major German employers is contributing to the disorganization of Germany's dual system of in-plant and sectoral negotiations. Subcontractors, subsidiaries and temporary agencies often have no collective bargaining institutions or are covered by different firm-level and sectoral agreements. As core employers move jobs to these firms, they introduce new organizational boundaries across the production chain and disrupt traditional bargaining structures. Worker representatives are developing new campaign approaches and using residual power at large firms to establish representation in new firms and sectors, but these have not been successful at rebuilding co-ordinated bargaining

Vertical Disintegration and the Disorganization of German Industrial Relations-super-1

Drawing on case studies from the telecommunications and auto industries, the authors argue that the vertical disintegration of major German employers is contributing to the disorganization of Germany's dual system of in-plant and sectoral negotiations. Subcontractors, subsidiaries and temporary agencies often have no collective bargaining institutions or are covered by different firm-level and sectoral agreements. As core employers move jobs to these firms, they introduce new organizational boundaries across the production chain and disrupt traditional bargaining structures. Worker representatives are developing new campaign approaches and using residual power at large firms to establish representation in new firms and sectors, but these have not been successful at rebuilding co-ordinated bargaining. Copyright Blackwell Publishing Ltd/London School of Economics 2007.