Nivo anti-VIP/gp120 antitela kod aktivnih sportista, pacijenata sa malignim bolestima i pacijenata sa HIV infekcijom

Abstract

Vazoaktivni intestinalni peptid (VIP) ima brojne biološke uloge u organizmu, deluje kao imunomodulator, vazodilatator, bronhodilatator, neurotransmiter i regulator genske ekspresije. VIP takoĎe ima vaţnu ulogu u kancerogenezi malignih oboljenja, jer deluje kao faktor rasta za ćelije karcinoma dojke i prostate, koje na svojoj površini eksprimiraju veliki broj VPAC1 receptora. Obzirom na učešće VIP-a u brojnim biohemijskim procesima u organizmu, njegov nivo u u cirkulaciji je pod strogom fiziološkom kontrolom, koja se ostvarje posredstvom prirodnih anti-VIP autoantitela. Ustanovljeno je da pacijenti inficirani HIV-om imaju povišen nivo neutrališućih anti-VIP/gp120 antitela u asimptomatskoj fazi bolesti. Anti- VIP/gp120 antitela usporavaju progresiju sindroma stečene imunodeficijencije (SIDE) i predstavljaju poslednju liniju odbrane organizma u HIV infekciji. NTM peptid iz konzerviranog C2 domena glikoproteina gp120 HIV virusa sadrţi epitop koji vezuje anti-VIP/gp120 antitela i ima visok stepen strukturne i informacione sličnosti sa VIP-om. NTM sadrţi aminokiselinski motiv FTD (Phe- Thr-Asp), koji je uključen u direktnu interakciju VIP-a sa VPAC1 receptorima. Ovaj domen glikoproteina gp120 ima strukturnu sličnost i sa drugim humanim proteinima uključujući i imunoglobuline, zbog čega ga imuni sistem prepoznaje kao sopstveni antigen. Molekularna mimikrija izmeĎu glikoproteina gp120 i ljudskih proteina osnovna je prepreka u dizajniranju vakcine, koja bi omogućila povećanu produkciju anti-VIP/gp120 antitela. Fizička aktivnost povećava nivo VIP-a u cirkulaciji, što za posledicu ima i porast anti-VIP/gp120 antitela i predstavlja jedini stimulans za produkciju ovih prirodnih autoantitela. Populacione i kliničke studije potvrdile su pozitivne efekte, koje fizička aktivnost ima u prevenciji nastanka tumora dojke i prostate, ali i u sprečavanju pojave recidiva u fazi remisije bolesti. Molekularni mehanizmi na kojima se zasniva protektivno delovanje fizičke aktivnosti još uvek su nepoznati. Polazeći od činjenice da profesionalni sportisti i osobe inficirane HIV-om, kod kojih je nivo anti-VIP/gp120 antitela povišen, imaju smanjen rizik od nastanka karcinoma dojke i prostate u poreĎenju sa opštom populacijom, moţe se pretpostaviti da ova antitela igraju značajnu ulogu u prevenciji ovih bolesti...

VIP is pleiotropic peptide exerting a wide range of biological activities, such as pulmonary and coronary vasodilatation, bronchodilation, antiinflammatory effects, immunomodulatory effects and regulation of gene expression. Also, VIP plays an important role in pathogenesis of breast and prostate cancer acting as an autocrine growth factor which up regulates the expression of vascular endothelial cell growth factor in cancer cells, carrying a large number of VPAC1 receptors on the cell surface. Involvement of VIP in numerous biochemical processes in the organism requires strong control of its level in the circulation, which is performed by natural anti-VIP antibodies. Therefore, it is reasonable to expect that the natural autoantibodies controlling VIP have an important protective role against breast and prostate cancer. Increased level of neutralizing anti-VIP/gp120 antibodies has been documented in HIV patients in its asymptomatic phase of disease. The studies indicate that anti-VIP/gp120 antibodies slow down AIDS progression and represent the last line of defense against the disease progression. The anti- VIP/gp120 antibodies bind to NTM peptide from the conserved C2 domain of the HIV glycoprotein gp120. The NTM peptide has high level of structural and informational similarities with VIP and encompasses the structural motif FTD (Phe-Thr-Asp), which is involved in direct interaction between VIP and VPAC1 receptor. Due to structural similarity between the C2 domain of the glycoprotein gp120 and other human proteins, including immunoglobulins, the immune system recognizes it as a self antigen. As a result of this molecular mimicry between the gp120 and host proteins, anti-VIP/gp120 antibodies cannot be induced with vaccination. The physical activity elicits anti-VIP/gp120 antibodies by increasing the level of VIP in circulation and therefore, represents the unique stimulus for production of these natural autoantibodies. Epidemiological and clinical studies confirmed positive effects of physical activity in prevention of breast and prostate cancer. Molecular mechanisms involved in protective role of physical activity are still elusive. Nevertheless, the fact that professional athletes and HIV-infected patients with increased level of anti-VIP/gp120 antibodies have lower incidence of breast and prostate cancer comparing to general population, indicates that these antibodies have significant role in prevention of these diseases...