To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

https://link.springer.com/content/pdf/10.1007%2Fs00134-017-4683-6.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.

/pdf/the-pathogenesis-of-rheumatoid-arthritis-5ec7s76zig.pdf

The pathogenesis of rheumatoid arthritis.

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Objective:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012.”Design:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host

/pdf/pyroptosis-host-cell-death-and-inflammation-4f2vauj8tx.pdf

Pyroptosis: host cell death and inflammation

Follicular lymphoma is the most common low-grade B-cell lymphoma. It is characterized by at least a partial follicular growth pattern in the majority of cases, by the morphological resemblance of the tumour cells to follicle centre centroblasts and centrocytes, and by the distinctive expression of Bcl-2 protein as a consequence of a translocation between chromosomes 14 and 18, resulting in the juxtaposition of Bcl-2 and the immunoglobulin heavy chain locus. It is not known whether the follicular growth pattern of follicular lymphoma is a consequence of properties of the tumour cells, or whether the tumour cells invade and gradually occupy a niche generated by a normal T-cell-dependent B-cell response. This study has identified cases of follicular lymphoma in which the tumour cells are apparent within a normal reactive germinal centre background. The reactive background has been investigated in these cases and also in cases showing a more characteristic appearance, in which entire malignant follicles appear to be Bcl-2-positive, as assessed by microdissection and analysis of clonality by the polymerase chain reaction (PCR). A reactive oligoclonal background was observed in all cases studied, characteristic of a normal follicle centre response. These data suggest that the progression of follicular lymphoma is dependent on the normal germinal centre microenvironment. Disruption of this dependence might be considered as a novel therapeutic strategy.

Relative distribution of tumour cells and reactive cells in follicular lymphoma.

Aim-To determine whether the immunoglobulin genes used by three gastric mucosa associated lymphoid tissue type lymphomas with known autoreactivity are mutated from germline as mutation from germline is an indicator of exposure to a mutational mechanism which characteristically acts on B cells as they undergo a follicle centre response.Methods-Cell lines established from two cases of MALT type lymphoma secrete autoantibodies recognising follicular dendritic cells (one case) and basement membrane (one case). The immunoglobulin heavy chain variable region genes (IgV(H)) and light chain variable region genes (IgV(L)) used by these cell lines, and the IgV(H) genes from a third case recognising human IgG were sequenced.Results-All three cases studied had mutated IgV(H) genes, while the IgV(L) genes were unmutated.Conclusion-The presence of mutations in IgV(H) genes is consistent with the origin of gastric MALT type lymphomas from B cells which have traversed the lymphoid follicle.

https://mp.bmj.com/content/molpath/49/1/M29.full.pdf

Sequence analysis of immunoglobulin variable region genes that encode autoantibodies expressed by lymphomas of mucosa associated lymphoid tissue.

It is crucial for the immune system to minimise the number of circulating mature self-reactive B cells, in order to reduce the potential for the development of autoantibody-related autoimmune diseases. Studies of animal models have identified two major checkpoints that ensure that such cells do not contribute to the naive B cell repertoire. The first is in the bone marrow as B cells develop and the second is in the spleen; B cells that are released from the bone marrow as transitional B cells go through more stringent selection in the spleen before they develop into mature naive B cells. Transitional B cells and their maturation have mostly been studied in mice. However, recent studies characterised human transitional B cells and found considerable differences to current models. In this review, we will consider these differences alongside known differences in mouse and human splenic function and ask whether human transitional B cells might develop along a different pathway.

Transitional B cells: how well are the checkpoints for specificity understood?

Monoclonal antibody (hml-1) labelling of t-cell lymphomas

Tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. Yet, if and how the tissue environment shapes the antigen specificity of iNKT cells remains unknown. By analysing iNKT cells from lymphoid tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for cells from various tissues resulting in differential lipid-antigen recognition. Within peripheral tissues iNKT cell recent thymic emigrants exhibit a different TCR repertoire than mature cells, suggesting that the iNKT population is shaped after arrival to the periphery. Consistent with this, iNKT cells from different organs show distinct basal activation, proliferation and clonal expansion. Moreover, the iNKT cell TCR repertoire changes following immunisation and is shaped by age and environmental changes. Thus, post-thymic modification of the TCR-repertoire underpins the distinct antigen specificity for iNKT cells in peripheral tissues.

Jo Spencer

Papers

Relative distribution of tumour cells and reactive cells in follicular lymphoma.

Sequence analysis of immunoglobulin variable region genes that encode autoantibodies expressed by lymphomas of mucosa associated lymphoid tissue.

Transitional B cells: how well are the checkpoints for specificity understood?

Monoclonal antibody (hml-1) labelling of t-cell lymphomas

Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells.