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Development of inflammatory diseases, such as metabolic syndrome and cancer, is prevalent in individuals that encounter continuous disruption of their internal clock. Further, daily oscillations in susceptibility to infection as well as a multitude of other immunological processes have been described. Much progress has been made and various mechanisms have been proposed to explain circadian variations in immunity; yet much is still unknown. Understanding the crosstalk between the circadian and the immune systems will allow us to manipulate clock outputs to prevent and treat inflammatory diseases in individuals at risk. This review briefly summarizes current knowledge about circadian rhythms and their role in the immune system and highlights progress and challenges in chrono-immunological research., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

Anti-Gal is the most abundant natural antibody in humans, constituting ~ 1% of immunoglobulins. Anti-Gal is naturally produced also in apes and Old World monkeys. The ligand of anti-Gal is a carbohydrate antigen called the 'α-gal epitope' with the structure Galα1-3Galβ1-4GlcNAc-R. The α-gal epitope is present as a major carbohydrate antigen in non-primate mammals, prosimians and New World monkeys. Anti-Gal can contributes to several immunological pathogeneses. Anti-Gal IgE produced in some individuals causes allergies to meat and to the therapeutic monoclonal antibody cetuximab, all presenting α-gal epitopes. Aberrant expression of the α-gal epitope or of antigens mimicking it in humans may result in autoimmune processes, as in Graves' disease. α-Gal epitopes produced by Trypanosoma cruzi interact with anti-Gal and induce 'autoimmune like' inflammatory reactions in Chagas' disease. Anti-Gal IgM and IgG further mediate rejection of xenografts expressing α-gal epitopes. Because of its abundance, anti-Gal may be exploited for various clinical uses. It increases immunogenicity of microbial vaccines (e.g. influenza vaccine) presenting α-gal epitopes by targeting them for effective uptake by antigen-presenting cells. Tumour lesions are converted into vaccines against autologous tumour-associated antigens by intra-tumoral injection of α-gal glycolipids, which insert into tumour cell membranes. Anti-Gal binding to α-gal epitopes on tumour cells targets them for uptake by antigen-presenting cells. Accelerated wound healing is achieved by application of α-gal nanoparticles, which bind anti-Gal, activate complement, and recruit and activate macrophages that induce tissue regeneration. This therapy may be of further significance in regeneration of internally injured tissues such as ischaemic myocardium and injured nerves., (© 2013 John Wiley & Sons Ltd.)

Signalling through the B cell antigen receptor (BCR) is required for peripheral B lymphocyte maturation, maintenance, activation and silencing. In mature B cells, the antigen receptor normally consists of two isotypes, membrane IgM and IgD (mIgM, mIgD). Although the signals initiated from both isotypes differ in kinetics and intensity, in vivo, the BCR of either isotype seems to be able to compensate for the loss of the other, reflected by the mild phenotypes of mice deficient for mIgM or mIgD. Thus, it is still unclear why mature B cells need expression of mIgD in addition to mIgM. In the current review we suggest that the view that IgD has a simply definable function centred around the basic signalling function should be replaced by the assumption that IgD fine tunes humoral responses, modulates B cell selection and homeostasis and thus shapes the B cell repertoire, defining IgD to be a key modulator of the humoral immune response.

Leukosialin or CD43 is a heavily O-glycosylated transmembrane protein expressed on all cells of the haematopoietic cell lineage with the exception of red blood cells and mature B cells. This antigen has been identified in human, mouse and rat with monoclonal antibodies. Although orthologues of many human and rodent leucocyte cell surface antigens have been described in recent years, CD43, despite its abundance on human and rodent cells, remained uncharacterized in other vertebrate species. The comparison of CD43 amino acid sequences from human, mouse and rat indicated a high level of homology in the cytoplasmic domain. A serum, (p.aCD43cp) raised against the recombinant cytoplasmic tail of the human CD43, was shown not only to recognize human CD43, but it bound to putative CD43 orthologues in many mammalian species. CD43 was found to be expressed in the same leucocyte subpopulations and circumstantial evidence suggested that CD43 is also regulated similarly during leucocyte ontogeny in all species investigated. As CD43+ cells were readily observed in fixed tissues, the p.aCD43cp serum may be used as a reliable reagent for the verification of the haematopoietic origin of infiltrations and, used together with other reagents, for the serological characterization of normal and pathological lymphoid tissues and lymphoid infiltrations in experimental work and in animal disease.

Immunoglobulin E is quantitatively a minor immunoglobulin class in serum, but nevertheless the major class of antibody mediating type I hypersensitivity reactions and hence, type I allergic phenomena. The bovine epsilon gene is one of the as yet uncharacterized mammalian immunoglobulin genes. We have therefore cloned and determined the cDNA sequence and genomic organization of the gene. It contains four constant region domain-encoding exons (CH1 to CH4) with a high homology to sheep C epsilon (87%) and to a lower degree to dog (62%), horse (58%), chimpanzee, orangutan, human (55%), mouse (52%) and rat (52%) C epsilon genes. Southern blot analysis of bovine genomic DNA, revealed the existence of a single C epsilon gene with a presence of allelic restriction fragment length polymorphism (RFLP).

Two monoclonal antibodies (mAb M4d2 and M4d3) specific for the alpha 2-fragment (C4d), and one antibody (mAb M4c3) specific for the gamma-chain of human complement protein C4, have been tested for cross-reactivity against mammalian complement. These mAb have also been found to react with C4 from guinea-pig (mAb M4d2 and M4c3) as well as from cattle, baboon and rhesus monkey (mAb M4d3 and M4c3) in an activation ELISA. Since reactivity of mAb M4d2 and M4c3 included guinea-pig complement, the specific recognition of mammalian C4 could be confirmed with sera from C4-deficient (def') guinea-pigs. mAb M4d2 or M4d3, but not mAb M4c3, stained glomerular deposits within renal tissue sections from pig, cattle and guinea-pig. In the case of mAb M4d2, specificity of that staining could also be demonstrated in kidney specimens from C4-def' guinea-pigs. It can be concluded that, as in humans, the C4d fragment is also present in mammalian glomeruli. Compared with normal guinea-pigs, the C4-def' and C2-def' animals showed markedly increased glomerular deposits of IgM. It appears that glomerular deposition of complement C4d in mammals: (1) indicates activation via the classical pathway; (2) represents a general phenomenon of renal homeostasis; and (3) seems to be involved in the physiological clearance of immune complexes.

A polyanion binding site was identified recently on human CD4 which is distinct from the human immunodeficiency virus (HIV)-gp120 binding region but which incorporates the first two immunoglobulin (Ig)-like domains of the molecule. To determine if this site is conserved in other species, several polyanions that blocked monoclonal antibody (mAb) binding to human CD4 were examined for their ability to inhibit the binding of mAb to mouse, rat, pig, sheep and chicken CD4. It was found that aurintricarboxylic acid (ATA) was a particularly effective inhibitor, blocking mAb binding to human, mouse, pig, sheep and rat CD4 by greater than 90% and to chicken CD4 by 80-90%. The polyanions dextran sulphate (DxS), polyvinyl sulphate (PVS) and polyanethole sulphonate (PAS) were also effective inhibitors of anti-CD4 mAb binding in most species, although there were clear species differences in the effects obtained. The polyanions did not inhibit mAb binding to a variety of other cell-surface antigens in the different species, with the exception of sheep CD8, suggesting that the inhibitory effects observed were essentially CD4 specific. Collectively these data indicate that a polyanion binding site is conserved in mammalian and avian CD4. Comparison of the amino acid sequences of human, mouse and rat CD4 revealed that basic residues in human CD4 which could participate in a polyanion binding site are conserved in mouse and rat CD4. It is proposed that this conserved polyanion binding site of CD4 interacts with a sulphated glycosaminoglycan chain which is associated with class II major histocompatibility complex (MHC) molecules containing recently processed antigen.