The immune system (enteric, gender, seasonality)

The following blog posts will discuss basic immune function and the possible connections with CPPS.

The immune system is divided in two arms: innate and adaptive. Both of which contain cellular (macrophages, natural killer cells etc) and humoral (antibodies) immune components. Cellular immunity protects mainly against intracellular bacteria, protozoans, fungi and many viruses), while humoral immunity protects against multicellular parasites, extracellular bacteria, certain viruses, ceratin toxins and allergens. A popular concept of immunity is the Th1/Th2/Th17-hypothesis.(1-3) In additon to these two arms, an oft forgotten an very important part of the immune system is the enteric immune system.

Not only does the gut have a massive nervous system (see below), it is also the biggest immune system in the body. The gut-associated lymphoid tissue comprises about 70 percent of the mucosal barrier (most of the rest protects the lungs). And that is not suprising as the gut has to withstand an endless stream of pathogens and occasional toxins. Not only invaders from outside the body but also the about over 100 trillion organisms that live in the gut. The maternal intestinal microbiota (both organisms and a large number of “intestinally derived bacterial components”, N.B. not antibodies, but genetic material) is passed to the newborn trough the breast milk.(4) Ingested probiotics may modulate intestinal pain and the immune system by normalizing cytokine ratios.(5)

The brain and the viscera communicate with each other to coordinate behavior and emotional responses (due to evolutionary reasons like territorial marking, not stop to pee while hunted, panic, anxiety, and so on).and visceral activity. Pathological changes (e.g. bacterial infection, tissue damage, distension of the colon and others) in the viscera affect the forebrain.

Immune activity shows a circadian rhythm with cellular/Th1 prevalence during sleep (maximum activity coincides with nocturnal cortisol maximum) and humoral/Th2 prevalence during daytime. Diseases more common / worse during daytime are e.g. stroke, arrhythmias, seizures, sepsis and asthma.

A seasonal pattern of increased immune activity during winter with humoral bias, to counter wintertime stress induced immune suppression, and cellular bias during summer is also postulated.(6,7) Children (and especially foetuses) are more humoral/Th2 biased than adults (8) (and sex differences are minimal before puberty). Adult men generally have a more Th1-biased response, due to high androgen levels, that gets more Th2-biased with age as testosterone levels decrease. Female response is generally more Th2-biased due to the high levels of estrogens that are both pro-inflammatory (a pro-fibrotic response) and “immunosupportive”. Thus the same infectious (or adjuvant) insult may cause a stronger anti-inflammatory response in men.(9)

Estrogens correlate with increased incidence of depression, axiety and auto-immune disorders (women are 2-9 times more likely to suffer from pain disorders, RA and SLE). Female immune response varies with the different phases of the menstrual cycle, pregnancy and contraceptive usage.(10)

Much confusion casued by animals studies arises from the fact that acute and chronic phase response are not distinguished. These differences between acute and chronic phases and phases of the menstrual cycle are seldom considered in general research even if sex differences have been accounted for (which in itself is not done as much as it should).

Nocturia induced sleep disruption and androgen alterations may both lead to immune changes worsening CPPS and explain the sickness behaviour seen in CPPS sufferers. Also the fact that CPPS generally remits during summer (when sun-stimulated vitamin D production shift the immune response towards an anti-inflammatory response), may indicate that CPPS is an immune related disorder. Possibly a disorder of Th1-driven (cellular) inflammatory immunity.

CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, enteric, gender immune dimorphism, immunity, Th1/Th2, androgens, estrogens, nocturia, seasonality.
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(1) Steinman L. A rush to judgment on Th17. J Exp Med 205(7): 1517–1522, 2008.
(2) Kidd P. Th1/Th2 balance: The hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8(3):223-246, 2003
(3) Steinman L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nature medicine 13(2):139-145, 2007
(4) Perez PF, Dore J, Leclerc M, Levenez F, Benyacoub J, Serrant P, Segira-Roggero I, Schiffrin EJ, Donnet-Hughes A. Bacterial imprinting on the neonatal immune system: lessons from maternal cells? Pediatrics 119(3):E724-732, 2007.
(5) Marchesi J, Shanahan F. The normal intestinal microbiota. Curr Opin Infect Dis 20:508-513, 2007.
(6) Nelson RJ, GE Demas GE, Klein SL, Kriegsfeld LJ. Seasonal Patterns of Stress, Immune Function, and Disease. Cambridge University Press, 2002.
(7) Nelson RJ. Seasonal immune function and sickness responses Trends in Immunology 25(4):187-192, 2004.
(8) Petrovsky N. Towards a unified model of neuroendocrine–immune interaction. Immunol Cell Biol 79:350–357, 2001
(9) Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 173:600-609, 2008.
(10) Darnall BD, Suarez EC. Sex and gender in psychoneurimmunology research: past, present and future. Brain Behav Immun 23:595-604, 2009.