Of Mosquitoes And Men - Immunology 101.

The immune system has two arms of attack: the cell mediated arm and the humoral arm. The following information details some specifics about how viruses effect women differently than men. Read on to learn more.
Each year as the tropical storm season worsens, torrential rainfall collects in every depression into which it falls, creating stagnating pools or water which mosquitoes delight in.

Malaria, transmitted by mosquitoes of several species, is among the world's top health problems. 3 million people die from malaria every year.

Before delving into the causes and potential cures, and looking at the role played by testosterone in suppressing the progression of malaria after a person is infected, a primer in immunology might be helpful.

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Immunology Primer

mosquito Here is Immunology 101 in a nutshell. The immune system has two "arms of attack": the cell mediated arm and the humoral arm.

The cell mediated arm, or cellular immunity, responds to general assaults on the body by sending out immune cells to do things like attack invading organisms, or degrade necrotic tissue, in a non-specific manner.

By 'non-specific,' it is meant that the immune cells do not recognize the invader as a specific target with which they are familiar.

Inflammation is an example of a cell-mediated response. When you get a sliver or strain a muscle the body sends immune cells there to wall off the site, increase blood flow, remove damaged tissue, etc.

Humoral immunity involves B lymphocytes that secrete antibodies that bind to the target and allow immune cells to recognize the target immediately as an invader and launch an attack.

When you are vaccinated for something, like smallpox, you are injected with a small inactive piece of the virus. This primes your body to make large numbers of B cell clones that, if ever challenged with smallpox for real, pump out antibodies that mark the virus for destruction by other cells.

The big advantage of this system is that it is fast and efficient. The disadvantage is that it is very specific. The cellular response is not as efficient but it works against any invader, not just one for which primed clonal B cells already exist.

Please note that this is a gross simplification, since in many diseases humoral and cellular immunity work together to tag and destroy invading organisms.

An important generalization must be made here. Invading organisms that have already entered cells within the body are targets for the cellular immune system. While circulating in the blood stream outside of cells (including blood cells) the pathogens are prone to attack by the humoral arm of the immune system.


Sex Hormones & The Immune System

There is an emerging model of how the sex steroids regulate the two arms of the immune system. It is thought that testosterone stimulates the humoral arm and suppresses the cellular arm. This paradigm arose from the study of autoimmune diseases which overwhelmingly plague women more than men.

The majority of autoimmune diseases involve a cellular immune system gone wild. Since in men testosterone suppresses cellular immunity, men are much less likely to suffer from these diseases, like rheumatoid arthritis. See Figure 1 below.

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So when one hears or reads that androgens are anti-inflammatory, this is kind of what it means technically. Some steroids seem to have stronger effects than others. When people say deca (nandrolone) improves joint health because it makes one hold water and lubricates the joints, this is likely not what is really happening.

It is an anti-inflammatory because it suppresses cell-mediated immunity, which controls inflammation. It has nothing to do with water.

Why is deca's reputation as an anti-inflammatory better than testosterone's, for example? My guess is the minimal aromatization and its progestogenic activity.

What Is Aromatization?
The conversion into one or more 'aromatic' compounds, characterized by increased chemical stability resulting from the delocalization of electrons in a ring system (as benzene) containing usually multiple conjugated double bonds. Whew, how's that for a chemistry review!

If you examine Figure 1 below, you will see a couple of interesting things:

  1. First, progesterone, like testosterone (T), stimulates humoral immunity (the TH2 mediated response in the graphic) and suppresses cellular immunity (TH1 response) and the inflammatory response. So progesterone has anti-inflammatory action.

  2. Second, estrogen exerts a biphasic effect. At low doses, it is pro-inflammatory, stimulating the TH1 arm of the immune system (cellular immunity) and inflammation.

    Deca then works both as an androgen and a progestin to quell inflammation. Testosterone, by virtue of its aromatization to estrogen is a less effective anti-inflammatory.

Hormonal Influences

Figure 1: Hormonal Influences.

T helper 1 (TH1) cells secrete pro-inflammatory cytokines and promote cell-mediated immune responses, whereas TH2 cells trigger antibody production. In multiple sclerosis (MS) and rheumatoid arthritis (RA), there are features characteristic of a TH1 immune response directed against auto antigens in the central nervous system and joints, respectively.

Pregnancy and systemic lupus erythematosus (SLE) favor a TH2 environment. Sex hormones (such as progesterone) that promote the development of a TH2 response antagonize the emergence of TH1 cells.

This may explain why in multiple sclerosis and rheumatoid arthritis disease symptoms improve during pregnancy, whereas in lupus, they do not. (Science, Vol 283, Issue 5406, 1277-1278, 26 February 1999.)

So, in summary, an overactive TH2 system (due to elevated testosterone) will suppress cell-mediated immunity which is under the control of TH1 cells.

Numerous animal studies have shown that the cytokine IFN-gamma is critical in controlling infection. Note from the graphic above that IFN-gamma is secreted by signals emanating from TH1 cells.


Studies

Since testosterone suppresses TH1 activity, we would expect to see in animals and in patients that low testosterone levels correspond to an increase in parasite clearance, and vice versa. This is exactly what has been observed in a recently published report.1

Patients in that report1 invariably presented themselves at clinics well after they had been infected. These patients had testosterone levels at about half the normal range. We will return to this point later.

In animal studies, administration of testosterone to Plasmodium chabaudi malaria-infected animals resulted in the death of these animals, which are normally capable of clearing the parasite on their own.2

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Returning to our observation made earlier (Patients in study #1 invariably presented at clinics well after they had been infected and these patients had testosterone levels at about half the normal range)1, it would be extremely unlikely that all these patients coincidentally had low T levels when they were bitten.

Rather, it is much more likely that the body itself lowered T levels as a result of the metabolic stress associated with the disease. This concept is bolstered by the fact that in the same patients' cortisol levels rose under the stress of the illness.

In general, decreased testosterone synthesis and release may be caused by a variety of factors. Activated immune cells called macrophages can secrete nitric oxide (NO), which at high concentrations can inhibit testicular steroidogenesis. Cortisol could act to inhibit testosterone secretion and/or signaling.

This observed drop in testosterone might represent an adaptive host response to prevent immunosuppression by higher testosterone levels. Recall from our discussion above about humoral versus cell mediated immunity that once the malaria-transmitting parasite (some species of Plasmodium) enters cells in the body, cell mediated immunity comes into play to eliminate the invading organisms.

Plasmodium:

    In the case of Plasmodium, this pathogen spends virtually its entire time living inside the body's cells-primarily red blood cells and the liver. It is then logical to anticipate that cellular immunity would be required to rid the body of Plasmodium.

    So we see that activated immune cells, macrophages for example, lower testosterone, since this lowered T would result in a milder case of the disease.

What Is A Macrophage?
Macrophages are cells found in the body that are responsible for the elimination of disease-causing germs (such as microorganisms, viruses, toxins, bacteria, and fungi), as well as dead cells and cellular debris.

    There is an emerging paradigm in epidemiology that suggests that diseases start out highly virulent but end up evolving into milder forms lest their victims die, leaving no hosts to colonize. This may very well be the case with the majority of malaria strains.

    Teleologically speaking, the malaria parasite Plasmodium sp. may be choosing to moderate the effects of its infection to ensure the survival of the host, who can then go on to infect others. Exactly how this process is effected is not well understood.

What Does Teleologically Mean?
Relating to the exhibition or discussion of design or purpose, especially in nature.

Toxoplasmosis:

    The same phenomenon of depressed testosterone is seen in other parasitic infections. One of the best studied is toxoplasmosis, caused by the protozoa Toxoplasma. In the case of this infection, researchers determined that the pro-inflammatory cytokine IL-1 beta, released by immune cells known as macrophages during the early phase of the disease, was capable of suppressing GnRH, LH and testosterone.3

    This is strikingly similar to malaria, where the cytokines produced during the early acute phase of the disease lower testosterone, in effect putting the brakes on inflammatory damage to organs such as the liver.

Leishmaniasis:

    As a third and final example of how sex determines the outcome of certain diseases, we will look briefly at leishmaniasis, an endemic tropical disease caused by Leishmania sp., an obligatory intracellular parasite. Men are more prone to suffer this infection, likely due to the discussion above, where we described how testosterone suppresses the arm of the immune system that attacks intracellular parasites.

    In an interesting experiment with animals, Travi et al4 reported the following:

      "Effect of Exogenous Administration of Hormones. The administration of the opposing sex hormones to male and female hamsters for 20 days prior to and throughout the course of L. (V.) panamensis infection altered the course of disease evolution. Female hamsters treated with testosterone developed larger cutaneous lesions than untreated females at all time points and in fact developed larger lesions than male animals.

      This difference in lesion evolution was observed from the 30th to the 90th day, when the experiment was terminated. Androgens had a more pronounced effect on females than estrogens did on males. Male animals treated with estrogens showed a tendency to develop smaller lesions than their untreated controls, but this was not statistically significant." See Figure 2 below.


Click Image To View Original Version.
Figure 2.
Effects of the administration of opposing sex hormones to male and female hamsters infected with L. (V.) panamensis. Recently weaned male hamsters (n = 8) received a subcutaneous implant (Compudose 200) that released approximately 240 µg of 17 ß-estradiol/day throughout the study period.

    Recently weaned female hamsters (n = 8) received intramuscular injections of 1 mg of testosterone enanthate (Testoviron-Depot) per hamster twice per week until 3 months p.i. Twenty days after initiation of the sex hormone treatment, the hamsters were inoculated with 106 L. (V.) panamensis stationary-phase promastigotes as described in Materials and Methods.

    Lesion evolution was determined as described in the legend to Fig. 1, and the results are expressed as the mean (± standard error of the mean) of the lesion size. Female animals treated with testosterone had significantly larger lesions than untreated females (P < 0.05) at all time points. There was no significant difference in lesion size between the estradiol-treated and untreated male animals.


Conclusion

On a rather sad finishing note, one can see from Figure 1 that the high levels of estrogen during pregnancy favor a TH2 environment, suppressing cellular immunity.

Malaria is a serious problem for pregnant women and their fetuses in tropical developing countries. It is estimated that malaria-induced low birth weight (LBW) may kill nearly 400,000 African infants each year.5

The potential upside is that women become resistant to pregnancy malaria over successive pregnancies as they acquire antibodies that recognize placental parasites, suggesting that the development of a vaccine is feasible.

It may be possible to use recombinant technology to develop such a vaccine modeled after the natural antimalarial antibodies.


Click Image To View Original Version.
Appendix A: Life Cycle Of The Malaria Parasite 'Plasmodium Sp.'

References

  1. Muehlenbein MP, Alger J, Cogswell F, James M, Krogstad D. "The Reproductive Endocrine Response to Plasmodium Vivax Infection in Hondurans." Am J Trop Med Hyg. 2005 Jul; 73(1):178-187.
  2. Mossmann H, Benten WP, Galanos C, Freudenberg M, Kuhn-Velten WN, Reinauer H, Wunderlich F. "Dietary Testosterone Suppresses Protective Responsiveness to Plasmodium Chabaudi Malaria." Life Sci. 1997; 60(11):839-48.
  3. Oktenli C, Doganci L, Ozgurtas T, Araz RE, Tanyuksel M, Musabak U, Sanisoglu SY, Yesilova Z, Erbil MK, Inal A. "Transient Hypogonadotrophic Hypogonadism in Males with Acute Toxoplasmosis: Suppressive Effect of Interleukin-1 Beta on the Secretion of GnRH." Hum Reprod. 2004 Apr; 19(4):859-66.
  4. Travi BL, Osorio Y, Melby PC, Chandrasekar B, Arteaga L, Saravia NG. "Gender is a Major Determinant of the Clinical Evolution and Immune Response in Hamsters Infected with Leishmania Spp." Infect Immun. 2002 May; 70(5):2288-96.
  5. Duffy PE. "Maternal Immunization and Malaria in Pregnancy." Vaccine. 2003 Jul 28; 21(24):3358-61.