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Autoimmunity and CP/CPPS

What is autoimmunity?

CP/CPPS may be the result of an autoimmune process OR a chronic inflammatory process that is maintained in CPPS patients as a result of a breakdown of immunoregulatory mechanisms in the immediate environment of the prostate. Classic autoimmunity is a complex biochemical process in which the body attacks itself. Scientifically:

"Autoimmune diseases are often manifested as organ inflammation with loss of function, and detectable autoreactive T cell and autoantibody responses. In the proper genetic context ... these parameters of autoimmunity can result from a single pivotal event: the induction of a strong and persistent T cell response for a foreign or unrelated self peptide that mimics the target self peptide." Reprod Immunol 1998 Feb, Mechanism of ovarian autoimmunity: induction of T cell and antibody responses by T cell epitope mimicry and epitope spreading. Garza et al

Some of the classic autoimmune diseases are systemic lupus erythematosus (SLE), Crohn's disease, diabetes, psoriasis, Reiter's disease, rheumatoid arthritis, glomerulonephritis, rheumatic fever, polymyositis, autoimmune thyroiditis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, scleroderma, and Sjogren's syndrome. Some other diseases, such as ulcerative colitis and multiple sclerosis, may have autoimmune components. Autoimmunity is a topic of research since much is not understood about this phenomenon. In 2000 new pathways which can lead to autoimmunity were uncovered.

Recently much currency has been given to the concepts of molecular mimicry and bystander activation. It is beyond the scope of this website to explain these complex phenomena other than to say that a one-time event, usually an infection or stressor of some sort, can leave behind a residual inflammation caused by the body's immune system mistakenly attacking the body's own tissues.

In researching autoimmunity and pelvic pain syndrome/prostatitis, rodents are used because it's fairly easy to induce autoimmune prostatitis in rodents by injecting them with cells from their male accessory glands (humans also have male accessory glands).

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What can cause autoimmune reactions?

So why would our bodies be attacking our prostates (or nearby urogenital tissues, like urethra, bladder or epididymis)? Researchers have identified a number of paths which may lead to autoimmunity:

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Hit-and-Run Infection

There are numerous studies in the scientific literature which prove the role of infection in autoimmunity. Viruses and bacteria are readily implicated. Reiter's disease can usually (but not always) be traced back to an infection of the genito-urinary tract or bowel. One of the classic symptoms of Reiter's is chronic prostatitis (as well as joint pain, conjunctivitis and other symptoms).

Apart from viruses and bacteria, parasites and even normal bacterial flora can provoke autoimmune diseases.

It is also possible that a persistent, ongoing infection can cause an autoimmune reaction, but usually no infection can be found. Curing any infection found may make no difference to an established autoimmune response.

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Toxic Exposure

We already know that some antibiotics can induce autoimmunity. Then in May 1999 it was reported that researchers had found that chemical exposures can cause genetic reshuffling -- activating part of the immune system to cause the symptoms of fatigue, rashes, muscle pain and a litany of other vaguely defined ills.

Howard Urnovitz, of the nonprofit Chronic Illness Research Foundation and California-based Calypte Biomedical Corp, thinks his theory could explain other chronic illnesses, from some cases of cancer to multiple sclerosis. He and colleagues, writing in the journal Clinical and Diagnostic Laboratory Immunology, published by the American Society for Microbiology, say that one component of the immune system allows cells to ''recognize'' bacteria, viruses or parasites that have invaded before. These so-called memory cells rearrange their DNA through a cut-and-paste process to match the invaders.

It is this ability to cut and paste DNA that Urnovitz thinks may get activated after exposure to chemicals. Studying Gulf War veterans, they found RNA in the serum. RNA is not supposed to be in the serum, which is the liquid that carries blood cells.

The basic genetic material is DNA, which ``codes'' for the production of proteins. But DNA cannot make proteins. It employs RNA to do this, but it had been thought that RNA could not survive outside a cell or virus.

There was no RNA in the serum of the 50 controls. Urnovitz thinks the RNA gets released when the immune system revs up its cut-and-paste reaction. He postulates that disease symptoms occur depending on what the cell does with this new RNA. If it reverses it to DNA, and places it near an oncogene, (cancer-causing gene), cancer can start. If the new RNA makes a protein that the body has never seen before, this can cause autoimmunity -- multiple sclerosis, lupus, diabetes and possibly chronic fatigue syndrome. If the RNA travels from the seminal fluid to the ovum (egg), this may result in birth defects.

Urnovitz thinks that the bits of RNA might act like a kind of virus. Some viruses are little more than bags of RNA. The floating RNA looked like it came from one region of one chromosome known as 22q11.2, which Urnovitz said was known as a ''hot spot'' for rearranged DNA.

Urnovitz postulates that these results suggest that genetic alterations in the 22q11.2 region, possibly induced by exposures to environmental (toxins) during the Persian Gulf War, may have played a role in the pathogenesis of Gulf War Syndrome. Read the abstract for this study.

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Physical Trauma

It is well known today that vasectomy can lead to an autoimmune reaction, especially orchitis (inflammation of one or both testicles), because of the possibility of exposing the body's tissues to sperm via the incisions used during the operation and possible sperm leakage thereafter. Here are studies to support this:

  1. Nippon Hinyokika Gakkai Zasshi 1999 Sep;90(9):763-8 Establishment of murine model of autoimmune male infertility. Sakamoto Y, Matsumoto T, Kumazawa J.
  2. Allerg Immunol (Paris) 1991 Apr;23(4):121-5 Immunological causes of male infertility. Hassoun S, Drouet M, Le Sellin J, Bonneau JC, Sabbah A

Similarly, it may be possible for other tissues in the male urogenital tract to become sensitized to sperm, PSA and other secretions. The "trauma" which allows secretions to get into places they shouldn't be could result from numerous things such sports injury, operative procedures and even Tantric sex practices (ejaculation suppressed by grasping penis - very unwise).

Note: Some mice can develop autoimmune prostatitis after having their thymus glands removed.

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Diet

Diet can play a role in the development of autoimmune diseases. Classic examples are coeliac disease and juvenile diabetes.

Experiments with rodents have also shown that diet can cause autoimmunity. Two groups of mice were raised in germ-free environments, one group given an elemental diet consisting of pure proteins, minerals and vitamins while the other was fed on normal food. The mice eating the normal diet had a far higher incidence of autoimmune disease.

See :J Immunol 1999 Jun 1;162(11):6322-30, The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice. Maldonado et al.

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Genetic Predisposition

It is well accepted now that the tendency to develop autoimmune reactions can run in families. There are many posters to the prostatitis newsgroup who have fathers with the disease or family members with other autoimmune diseases. A man with a twin brother who suffers the disease has written of his experiences. Genetic predisposition has been demonstrated in mice too. For instance, diabetic mice have background genes which favour severe autoimmune manifestations, including prostatitis, irrespective of the target tissue:

  1. J Exp Med 2000 Jan 17;191(2):313-20, Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. Horai et al.
  2. J Autoimmun 1998 Dec;11(6):603-10. Non-obese diabetic (NOD) mice are genetically susceptible to experimental autoimmune prostatitis (EAP). Rivero et al.

Lastly, certain breeds of genetically susceptible mice developed spontaneous autoimmune lesions of the genito-urinary tract even when raised in a germ-free environment. It's interesting that these mice develop lesions in their bowels and genito-urinary system. It appears that the urogenital tract is a weak point in mammals, prone to manifest autoimmune disease.

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Stress

The field of psychoneuroimmunology is in its infancy, but several studies have linked the onset and severity of autoimmune diseases to psychological stress. See, for example: Annu Rev Psychol 1996; 47: 113-42 Health psychology: psychologic factors and physical disease from the perspective of human psychoneuroimmunology. Cohen et al.

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Studies linking Autoimmunity to CP/CPPS

New in 2002:

Cytokine Polymorphisms in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Association with Diagnosis and Treatment Response. Shoskes DA, Albakri Q, Thomas K, Cook D. J Urol 2002 Jul;168(1):331-335

Autoimmune T cell responses to seminal plasma in chronic pelvic pain syndrome (CPPS), Batstone GR, Doble A, Gaston JS. Clin Exp Immunol 2002 May;128(2):302-7

CHRONIC PROSTATITIS: CASE BUILDS FOR AUTOIMMUNE COMPONENT

Prostatic inflammation may exist even without the presence of bacteria, viruses, and leukocytes - UROLOGY TIMES, November 1998

Mac Overmyer, Contributing Editor

Baltimore- A team of researchers here has uncovered evidence suggesting that some cases of chronic prostatitis/chronic pelvic pain syndrome may in fact be autoimmune disease, perhaps originating from earlier bacterial infection.

Richard B. Alexander, MD, and colleagues from the University of Maryland and the Veterans Affairs Maryland Health Care System found elevated levels of tumor necrosis factor alpha (TNFa) and interleukin-1 beta (IL-ib) in the seminal fluids of men with the syndrome.

"This suggests a continuing inflammatory process that can become active even in the absence of bacteria, viruses, or leukocytes," said Dr. Alexander, associate professor in the university's division of urology and chief of urology for the VA Maryland Health Care System.

Last year, Dr. Alexander showed that T-cells from some men with the syndrome reacted to normal prostatic proteins, which also suggests a strong autoimmune component to the syndrome (Urology 1997; 50:893-9).

Identifying the process underlying prostatitis in even a small percentage of patients would be welcome news. The condition accounts for an estimated 2 million office visits annually, but bacterial infection is identified as a causative entity in no more than 10% of cases. Empiric treatment with antimicrobial agents is a standard approach.

These treatments can be long and expensive and carry the inherent risk of creating resistant organisms. Moreover, the benefits of such therapy have yet to be shown. The evidence of autoimmune disease is far from conclusive, but if it can be shown that some cases originate in the immune system, these men might benefit from investigational agents that reduce inflammation by blocking the actions of cytokines such as TNFa.

Dr. Alexander's group identified 18 patients with a mean age of 38 who were diagnosed with chronic prostatitis/chronic pelvic pain syndrome. All patients presented with pelvic pain lasting longer than 3 months associated with voiding symptoms and sexual dysfunction, and all had been pretreated with antimicrobial therapies.

Seminal fluid was obtained from the 18 patients as well as eight normal, healthy volunteers. The mean level of TNFa in the men with the syndrome was 98 pg/mL compared with 17 pg/mL in the normal volunteers (p=.O39). The mean level of IL-1b was 246 pg/mL in the prostatitis patients and 27 pg/mL in the volunteers (p=.OO2).

DON'T COUNT ON LEUKOCYTES

The researchers noted that while the number of leukocytes per high-power field in expressed prostatic secretions (EPS) can provide evidence of prostatic duct inflammation, they found no correlation between leukocyte counts and cytokine levels.

One intriguing observation was that no leukocytes could be found in the EPS of the patient with the highest cytokine levels. Conversely, some patients with higher than average leukocyte counts had cytokine levels comparable with those seen in the normal volunteers.

These findings are "further evidence the number of leukocytes in EPS cannot reliably distinguish a meaningful sub-population of symptomatic patients with chronic prostatitis/chronic pelvic pain syndrome," the team reported.

Dr. Alexander isn't surprised by the absence of a correlation with leukocytes.

"These cytokines-seen in other inflammatory diseases such as rheumatoid arthritis and Crohn's disease-are secreted by monocytes," he told Urology Times. "The inflammation is in the tissue, not the ducts."

Measuring cytokine levels in symptomatic men could be a means of objectively classifying disease severity and categorizing subgroups of patients for specific therapies, Dr. Alexander said.

In turn, cytokine-inhibiting therapies may be a way of confirming whether or not some cases of prostatitis represent autoimmune disease. If the agents are proven to be clinically effective and if symptoms resolve when they are applied, the case for autoimmune disease would be more clearly established.

Dr. Alexander's research was supported by grants from the National Institute of Diabetes, Digestive and Kidney Diseases and the U.S. Department of Veterans Affairs.

CHRONIC PROSTATITIS: CASE BUILDS FOR AUTOIMMUNE COMPONENT Part II


Histologic, immunohistochemical findings point to inflammatory reaction that may be cell-mediated - UROLOGY TIMES, November 1998


Richard R. Kerr, Editor-in-Chief

Zurich, Switzerland: So-called noninflammatory chronic pelvic pain syndrome (NI-CPPS), the most common form of chronic prostatitis, may be an inflammatory reaction after all and appears to be cell-mediated, suggests research by Swiss urologists.

In a prospective study, they found inflammatory expressions in serum-complement, serum-interleukin, and sperm-interleukin concentrations in men with chronic pelvic pain syndrome. Corresponding immunohistochemical findings showing a large number of T cells, together with an absence of B cells, suggest that the condition is cell-mediated, they concluded.

"Until now, if patients had prostates with pain and no evidence of any inflammation or infection, this was the definition of noninflammatory chronic pelvic pain syndrome," Hubert John, MD, told Urology Times. "We were able to show that there is an inflammatory reaction, even in patients with noninflammatory chronic pelvic pain syndrome. And there is probably a chronic autoimmune reaction explaining the complaints, the pain, and lack of success with medications these patients have tried."

Dr. John, a urologist at Zurich University Hospital, is currently a research fellow in the department of pathology at the SUNY Health Science Center in Syracuse, NY He worked under Dieter Hauri, MD, professor of urology at University Hospital, on this study.

To search for immunopathologic patterns in patients with NI-CPPS, the researchers evaluated 88 men (mean age, 42) who had been referred to the university's prostatitis outpatient clinic. A control group consisted of nine men (mean age, 53) who were seen for testicular or scrotal conditions and who consented to prostate biopsies.

Typical of many men with chronic prostatitis, patients in the study had sought treatment from one to seven physicians prior to their clinic visit and had received previous antibiotic treatment for 1 to 10 months (mean, 3 months).

During the 9-month course of the study, all patients under-went fractionated urinary cultures, including expressed prostatic secretions (EPS) twice. Serum, urine, and ejaculate studies were performed three times in monthly intervals.

Among 50 patients in whom complete sampling of urinary, serum, and sperm probes was achieved, NI-CPPS (defined as <20 leukocytes in the high-power field of EPS) was observed in 44. Immunofluorescence of T lymphocytes and B lymphocytes was performed on 71 biopsy samples from chronic prostatitis patients and 25 samples from patients without symptoms or obstruction.

Dr. John's initial data, presented at the AUA meeting in San Diego, showed that intra-acinary T lymphocytes were present significantly more often in NI-CPPS patients than in healthy controls (p=.05). In the stroma, there was no difference in T lymphocytes between the patients and controls.

Further, division of T lymphocytes by T-helper (CD4) and T-suppressor (CD8) cells showed a much higher number of T-suppressor cells (p=.0001).The presence of B lymphocytes was no different between the two groups, either in the gland or in the stroma.

In subsequent analysis of the data, Dr. John correlated these histological findings to the presence of cytokines in serum and in sperm (IL-la, IL-2, IL-6, C3c, and C4). The control group for semen analysis consisted of 96 normal ejaculate samples according to the WHO criteria without sperm infection.

"Concentrations of these tissue repair and inflammatory factors did correlate to the amount and activity of T cells in the epithelial layer. So we can propose that these inflammation factors are produced from T cells," Dr. John said.

Dr. John said the next step in confirming an autoimmune etiology for CP/CPPS would be a controlled immunosuppressive therapy trial.

See also: Urology 1997 Dec;50(6):893-9, Autoimmune prostatitis: evidence of T cell reactivity with normal prostatic proteins. Alexander RB, Brady F, Ponniah S.

Identification of high-titer autoantibodies to prostate-associated antigens in some patients with chronic abacterial prostatitis. R. Trammell, T. Jewett, D.E. Neal, E.J. Moticka, B. Wolters (Unpublished)


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Treatments

One of the only chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) patients to have achieved a verified, long-term and complete remission is a kidney transplant patient who underwent full immunosuppression (see Palapattu GS, Shoskes DA. Resolution of the chronic pelvic pain syndrome after renal transplantation. J Urol. 2000 Jul;164(1):127). Of course this treatment is not practical for the vast majority of CP/CPPS patients.

Some immunosuppressive drugs are still untried, like Mycophenolate mofetil, cyclosporin A and newer drugs which directly modify aspects of the immune system's response.

Quercetin - a bioflavonoid that decreases inflammation and oxidant stress in the prostate while increasing local concentrations of beta-endorphins - is extremely effective in controlling symptoms for many patients. Quercetin has also been shown to inhibit the induction and function of T cells in vitro, so it may be able to short-circuit the root cause of autoimmunity. Its general properties are: anti-oxidant, tyrosine kinase inhibitor, nitric oxide inhibitor, anti-inflammatory (inhibits NF-kB).

Antibiotics are often useful in subduing inflammation, even when no infection is present. Research in the last 15 years has shown that antibiotics are both anti-inflammatory and immunomodulatory agents. The dangers of recurrent and long-term antibiotic use outweigh the positive results some patients experience, in the view of many.

The future hope is for drugs which target genes, or drugs which target increasingly refined subsections of the immune sytem.

For those who favor allopathic medicine, here are some general recommendations for autoimmunity: "Eat a low-protein, high-carbohydrate diet. Eliminate milk and milk products, including commercial foods made with milk. Minimize consumption of foods of animal origin. Avoid polyunsaturated vegetable oils of all kinds, but use omega-3 oils such as flax oil and anti-inflammatory oil capsules such as fish oil. Be sure to do regular aerobic exercise. Practice relaxation techniques. Visualization can be very effective at moderating autoimmune responses. Psychotherapy can be valuable as an aid to changing emotional states that keep the immune system off balance. Hypnotherapy is also useful if you can find a hypnotherapist willing to take on autoimmune disease. Protect your immune system. All autoimmune diseases tend to follow patterns of exacerbation and remission, and the potential for remission is always there. The ups and downs of these conditions often mirror the ups and downs of emotional life, so it is worth cultivating positive mental states and working with practitioners who encourage you to experiment and try to manage your own health."

Warning

Avoid infections which can set off autoimmune reactions. If you are genetically susceptible to such reactions you may find yourself with more and more area areas of pain and inflammation in your body. For example, chronic aseptic sinusitis is commonly found in the chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) population (source: sci.med.prostate.prostatitis newsgroup).

Extra reading: a fascinating study in the journal Nature links salmonella to arthritis.

Dr Shoskes has his own dissenting view on autoimmunity and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

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