Miranda K. Adelman

Evolutionary factors in the emergence of the combinatorial germline antibody repertoire.

Although life began on earth approximately 3.5 billion years ago, the combinatorial immune response apparently arose in a “big bang” approximately 450 million years ago, [1–4] coincident with the emergence of jawed vertebrates. Preceding this event was the so-called Cambrian explosion occurring approximately 545 million years ago that resulted in the seemingly rapid appearance of virtually all living forms as represented by the fossil record [5, 6]. However, molecular investigations seeking to calibrate evolutionary clocks and analyze phylogenetic relationships indicate that the explosive phases of evolution implied by the fossil record may have been preceded by extended periods of inconspicuous innovation [5, 6] in possible living organisms thatdid not become part of the currently available fossil record. The necessary elements of the combinatorial immune system, immunoglobulins (Igs), T-cell receptors (TCR), MHC products and recombinase activator genes (RAG) are clearly present in even the most primitive jawed vertebrates, the chondrichthian fishes [7–10] which appeared in evolution approximately 450 million years ago. Definitive evidence for these elements is thus far lacking in agnathan vertebrates and in lower deuterostomes. Nevertheless, many primordial elements upon which the combinatorial system is built may well have preceded the split in evolution between protostomes and deuterostomes and their origins may even extrapolate back to ancient times corresponding to the origin and evolution of bacteria.

The Natural Antibody Repertoire of Sharks and Humans Recognizes the Potential Universe of Antigens

In ancestral sharks, a rapid emergence in the evolution of the immune system occurred, giving jawed-vertebrates the necessary components for the combinatorial immune response (CIR). To compare the natural antibody (NAb) repertoires of the most divergent vertebrates with the capacity to produce antibodies, we isolated NAbs to the same set of antigens by affinity chromatography from two species of Carcharhine sharks and from human polyclonal IgG and IgM antibody preparations. The activities of the affinity-purified anti–T-cell receptor (anti-TCR) NAbs were compared with those of monoclonal anti-TCR NAbs that were generated from a systemic lupus erythematosus patient. We report that sharks and humans, representing the evolutionary extremes of vertebrate species sharing the CIR, have NAbs to human TCRs, Igs, the human senescent cell antigen, and to numerous retroviral antigens, indicating that essential features of the combinatorial repertoire and the capacity to recognize the potential universe of antigens is shared among all jawed-vertebrates.

Autoantibodies to the δ-Opioid Receptor Function as Opioid Agonists and Display Immunomodulatory Activity

In this report, we show that affinity purified human anti-delta opioid receptor (DOR) autoantibodies from IVIG are specific to DOR and possess agonistic properties displayed by their ability to dramatically decrease forskolin stimulated cAMP accumulation. Anti-DOR autoantibody also caused phosphorylation of the opioid receptor. Anti-DOR autoantibody treatment showed a significant reduction in CXCR4 gene expression as well as surface protein expression. In contrast, anti-DOR autoantibody treatment significantly upregulated CCR5 gene and protein expression. The presence of anti-DOR autoantibodies in IVIG and their potent immunomodulatory activity is further evidence to support the cross-talk between the neuroendocrine and immune systems.

23 – Endogenous Retroviruses as Etiological Agents in Systemic Lupus Erythematosus

With regard to retroviral mediators of autoimmune/inflammatory diseases, coupled with genetic and environmental factors, it is clear that retroelements, in particular human endogenous retroviruses (HERVs), play a vital and significant role in the etiopathogenesis of such diseases. Because of the genetic diversity of exogenous and endogenous retroviruses, it has been difficult to delineate or identify specific retroviruses associated with specific autoimmune or inflammatory diseases. However, sequencing of the human genome and genome-wide scans of both humans and mice support the hypothesis of a HERV based etiopathogenesis for systemic lupus erythematosus (SLE). Specifically, it is proposed that molecular mimicry between the Gag-related region of (U1)snRNP and HRES-1 initiates the production of cross-reactive auto-antibodies and associated immune complexes. In addition to molecular mimicry, other mechanisms of autoimmunity brought about by HERVs include but are not limited to insertional mutagenesis, superantigen-type activity, cis- or trans-regulation of cellular genes, and immunomodulation by HERV gene products. Continued research in the field of autoimmune disease and HERVs as etiological factors will certainly facilitate the understanding of the very complex disease, SLE, as well as other autoimmune or inflammatory diseases.