Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

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Sex differences in immune responses

Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Immunology of multiple sclerosis

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

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The immunology of stroke: from mechanisms to translation

Regulatory T cells (Tregs) and the PD-1: PD-ligand (PD-L) pathway are both critical to terminating immune responses. Elimination of either can result in the breakdown of tolerance and the development of autoimmunity. The PD-1: PD-L pathway can thwart self-reactive T cells and protect against autoimmunity in many ways. In this review, we highlight how PD-1 and its ligands defend against potentially pathogenic self-reactive effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (i) the promotion of Treg development and function and (ii) the direct inhibition of potentially pathogenic self-reactive T cells that have escaped into the periphery. Treg cells induced by the PD-1 pathway may also assist in maintaining immune homeostasis, keeping the threshold for T-cell activation high enough to safeguard against autoimmunity. PD-L1 expression on non-hematopoietic cells as well as hematopoietic cells endows PD-L1 with the capacity to promote Treg development and enhance Treg function in lymphoid organs and tissues that are targets of autoimmune attack. At sites where transforming growth factor-beta is present (e.g. sites of immune privilege or inflammation), PD-L1 may promote the de novo generation of Tregs. When considering the consequences of uncontrolled immunity, it would be therapeutically advantageous to manipulate Treg development and sustain Treg function. Thus, this review also discusses how the PD-1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD-1: PD-L modulation.

The PD-1 pathway in tolerance and autoimmunity

Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

Antigen-Specific Immunotherapy Protects Optic Nerve from Inflammation and Demyelination in Humanized HLA-DR2 Mice with Optic Neuritis

Arthur A. VandenbarkHalina Offner, Yoram Reiter, Gregory G. Burrows andMooney, Rony Dahan, Nerri Duvshani, Richard Bucala, Roberto Meza-Romero, Gil Benedek, Xiaolin Yu, Jeffery L.ol.1303118http://www.jimmunol.org/content/early/2014/03/28/jimmunJ Immunol€ published online 28 March 2014MaterialSupplementary8.DCSupplemental.htmlhttp://www.jimmunol.org/content/suppl/2014/03/30/jimmunol.130311Subscriptionshttp://jimmunol.org/subscriptionsInformation about subscribing to The Journal of Immunology is online at: Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at: Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:

Autoimmune Encephalomyelitis Expression and MIF Effects in Experimental 1 Constructs Block CD74 α HLA-DR

Lewis, or BN origin were used along with whole BP in the selection culture. After the establishment of stable lines, we tested the fine specificity of each line to BP peptides to learn whether the APC genotype could influence the identity of the immunodominant epitopes. To investigate the clinical consequences of epitope im- munodominance, we inoculated rats with the various lines. The results indicate that the genome of the APC can influence the immunologic dominance of BP epi- topes, and epitope immunodominance

Experimental autoimmune encephalomyelitis mediated by t influences immunodominant epitope of basic protein' lymphocyte lines: genotype of antigen-presenting cells

Low concentrations of antibrain antibody can be detected in cerebrospinal fluid (CSF) from most patients with multiple sclerosis and a few patients with other neurologic diseases.

Antibrain antibody adsorption on microtitre plates

Both the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients and synovial fluid (SF) from rheumatoid arthritis (RA) patients demonstrate increased lymphocyte infiltration and production of immunoglobulin of multiple specificities. To explore the possibility that antibodies present in these widely separated compartments share similar or identical specificities, reactions of CSF and SF with extracts of brain and synovial tissue or with purified antigens were compared by the enzyme linked immunosorbent assay (ELISA). CSF and SF showed significant reactivity to both of the tissue extracts as well as to myelin basic protein (MBP) and keyhole limpet haemocyanin (KLH). The reactivity to MBP of CSF and SF was inhibitable by preincubation with specific rabbit antibody, suggesting that the same or closely associated determinants were recognized by antibodies in both fluids and by the rabbit antibodies. In additional experiments, reactivity of pooled CSF or SF to chromatofocused fractions of brain or synovial tissue extracts revealed similar reaction patterns, although each fluid reacted distinctly with at least one fraction of each extract. These results support the suggestion that a common deregulation process in MS and RA stimulates non-selectively a large repertoire of B-cell clones to produce ‘nonsense’ immunoglobulins to many antigens, including some presumably not found in the respective tissue compartments. Responses to disease-associated ‘target’ antigens are difficult to discern, but may be detectable in CSF or SF reactions to fractions of crude tissue extracts.

Arthur A. Vandenbark

Papers

Antigen-Specific Immunotherapy Protects Optic Nerve from Inflammation and Demyelination in Humanized HLA-DR2 Mice with Optic Neuritis

Autoimmune Encephalomyelitis Expression and MIF Effects in Experimental 1 Constructs Block CD74 α HLA-DR

Experimental autoimmune encephalomyelitis mediated by t influences immunodominant epitope of basic protein' lymphocyte lines: genotype of antigen-presenting cells

Antibrain antibody adsorption on microtitre plates

Shared antibrain specificities of cerebrospinal fluid and synovial fluid antibodies