Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm

The adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses

Adhesion receptors of the immune system.

Sepsis is the leading cause of death in critically ill patients in the United States. Yet the individual host response to septicemia is variable, depending on the patient's immune response, age, nutritional status, and coexisting conditions, as well as on the virulence of the organism and the size of the inoculum. This review examines evolving concepts of sepsis and discusses new and potential therapies. Recent clinical advances include therapy with activated protein C, stringent control of blood glucose, and early goal-directed therapy to treat cellular oxygen deficit. Future therapies may be focused on modulating the immune response in the light of the characteristics of the specific pathogen, the genetic profile of the patient, and the duration of the disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMra021333

The pathophysiology and treatment of sepsis.

Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity

Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NF kappa B. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.

CpG Motifs in Bacterial DNA and Their Immune Effects

α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1

Identification of a murine Peyer's patch—specific lymphocyte homing receptor as an integrin molecule with an α chain homologous to human VLA-4α

The 89-kDa cell surface glycoprotein, P3.58, is detectable on advanced human melanomas in situ but not on benign melanocytes or early melanomas. cDNA cloning of P3.58 from melanoma cells was accomplished by screening a lambda zap expression vector library with monoclonal antibodies produced against the denatured antigen. Nucleotide sequencing of the clones revealed that P3.58 is identical to the intercellular-adhesion molecule 1. No qualitative differences in P3.58 mRNA species could be seen between melanoma cells and hematopoietic cells and no differences in gene organization were observed between peripheral blood leukocytes and melanoma cells. Inspection of the deduced amino acid sequence of P3.58 indicated the presence of the consensus sequence characteristic for complement-binding proteins. The acquisition of this cell-adhesion molecule during the process of tumor progression is speculated to contribute to the development of metastasis in melanoma.

http://www.pnas.org/content/86/2/641.full.pdf

De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis

Lymphocytes home to various lymphoid organs by adhering to and migrating through specialized high endothelial venules (HEV) The murine cell surface heterodimer LPAM-1 is involved in the homing of lymphocytes to mucosal sites (Peyer's patches) LPAM-1 has an alpha subunit (alpha 4m) analogous to the alpha chain of the human integrin molecule VLA-4 Here we show that the LPAM-1 beta subunit (beta p) is immunochemically and biochemically distinct from previously defined integrin beta subunits, suggesting that beta p represents a novel integrin beta subunit Depending on the cellular source two alternative beta subunits, beta p and integrin beta 1, can be isolated in association with alpha 4m Therefore, alpha 4m is the common subunit of the unique integrin LPAM-1 (alpha 4m beta p) and of the heterodimer LPAM-2 (alpha 4m beta 1), which is analogous to VLA-4 Antibody-blocking experiments suggest that, in addition to LPAM-1, LPAM-2 is also involved in the organ-specific adhesion of lymphocytes to Peyer's patch HEV

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1989.tb03566.x

Peyer's patch-specific lymphocyte homing receptors consist of a VLA-4-like alpha chain associated with either of two integrin beta chains, one of which is novel.

Background: In recent models, compensatory antiinflammatory immune reactions triggered in response to systemic inflammation were considered important for the outcome of sepsis. The present study investigated T-cell functions in patients with postoperative sepsis due to intra-abdominal infection. Methods: Peripheral T cells were purified from 32 sepsis patients and 41 healthy controls. Proliferation and production of interferon (IFN)-γ, interleukin (IL)-2, IL-4, tumor necrosis factor (TNF), and IL-10 were stimulated by cross-linking of CD3 and CD28. Results: T-cell proliferation and production of IL-2 and TNF were severely suppressed in patients with lethal intraabdominal infection as compared with survivors and healthy controls. Sepsis survivors showed normal T-cell proliferation and IL-2 release, whereas secretion of TNF was reduced. However, TNF suppression in survivors was less severe than in nonsurviving patients. Defective T-cell functions were observed at the onset of sepsis and persisted throughout the entire observation period. T-cell production of IL-4 and IL-10 was not affected by postoperative intraabdominal infection. Conclusions: Defective T-cell proliferation and secretion of IL-2 and TNF correlate with sepsis mortality, thus indicating an important role of T cells for the immune defense against postoperative infection. Immune defects were evident at the onset of sepsis, suggesting that immunosuppression may develop as a primary response to sepsis without preceding immune hyperactivity.

Bernhard Holzmann

Papers

α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1

Identification of a murine Peyer's patch—specific lymphocyte homing receptor as an integrin molecule with an α chain homologous to human VLA-4α

De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis

Peyer's patch-specific lymphocyte homing receptors consist of a VLA-4-like alpha chain associated with either of two integrin beta chains, one of which is novel.

Selective defects of T lymphocyte function in patients with lethal intraabdominal infection