The Natural Selection of Psoriasis: the Epidemiological Evidence

The prevalence of an inherited disease may in part be related to the response conveyed by these genes to an environmental hazard. An example of this is the high frequency of the sickle cell gene in some areas of Africa, which confers protection to malaria among its carriers. Psoriasis has a strong genetic component--there is a positive family history in 71% of affected children.[7] But the prevalence has a marked global variation. The variation of high and low psoriasis prevalence appears to mirror closely the historical incidence of mortality from epidemics of invasive streptococcal infections. Although these infections, such as scarlet fever and erysipelas, no longer cause high mortality, they were a major cause of death before improvement in nutrition, housing and the introduction of antibiotics. In the 19th century scarlet fever was the commonest cause of childhood mortality in the U.K. Between 1861 and 1870 the average annual mortality in the under 15-years age group in England and Wales was 2617 per million.[8] Thus, for every million children surviving to the age of 15 years, approximately 40 000 would have died from scarlet fever. Scarlet fever epidemics could take a malignant course, and kill up to 30% of those affected. One such epidemic was responsible for 50 000 deaths, representing a quarter of the indigenous population of a Chinese town where the disease had not existed in living memory.[9] The extensive numbers of deaths resulting from epidemics of systemic streptococcal infection would be sufficient to provide a natural check on survival of the human host.

There are perhaps four key observations regarding the epidemiology of psoriasis (Fig. 1). 1. The prevalence of psoriasis is highest in Northern Europe, being estimated at 2-3%.[6] Likewise, the highest global incidence and mortality from scarlet fever was in Northern Europe.[8] 2. Psoriasis is generally commoner in temperate climates, even within a single country such as China. In the northern province of Heilongjian the prevalence of psoriasis is 16 times greater than that seen in the southern province of Guangxi.[10] Yet again we see a similar pattern with historical mortality from scarlet fever, which has been much higher in northern regions of China, where it has occurred in epidemics.[1] A League of Nations report describes scarlet fever as a disease of temperate climates, being especially prevalent in countries of the north and rare in the tropics.[11] 3. Among aboriginal groups absence of psoriasis correlates with a historical absence of mortality from streptococcal disease. Pure American Indians have little or no psoriasis.[12] It is widely believed they migrated to America through the Bering Straits. Studies of isolated Inuit/Eskimo communities revealed no history of streptococcal disease or scarlet fever before contact with Europeans,[13,14] and psoriasis is also rare in Greenland Inuit.[15] Similarly, psoriasis is rare in Australian Aborigines,[16] who were not subjected to streptococcal systemic infection until this was introduced by Europeans in the last 200 years.[17] Perhaps an important aspect of streptococci is their poor ability to survive outside the host (either human or animals). They would therefore be more likely to fare better in farming or urbanized communities compared with hunter-nomadic tribes where the spread of new strains from carriers would be more difficult to achieve. 4. Geographical differences in psoriasis prevalence appear to be more closely related to genetic rather than environmental effects, as migrating populations have retained their original prevalence rates for psoriasis. In the U.S.A., the black population, having originated from West Africa where there has been a low incidence of invasive streptococcal disease, has retained a low prevalence of psoriasis, while the white population, originating from Europe where streptococcal epidemics were common, has a high prevalence of psoriasis.[18] Psoriasis was found to be 30 times commoner in Europeans living in Java compared with the native population.[19] Historically, scarlet fever was not a recognized disease in the Javanese before colonization.[20]

(Enlarge Image) Figure 1. Epidemiological evidence for the natural selection of psoriasis. 1. Prevalence of psoriasis is highest in Northern Europe; historical mortality rates from invasive streptococcal infections are also highest in Northern Europe. 2. Within one country (China) prevalence rates of psoriasis are highest in northern provinces compared with southern provinces; historical rates of mortality from streptococcal epidemics mirror this pattern, with high mortality rates in the northern provinces only. 3. Aboriginal races, e.g. Australian, Arctic Inuit have little or no psoriasis; mortality from streptococcal epidemics has occurred only recently, since after contact with Europeans. 4. Prevalence rates of psoriasis among populations are due to genetic rather than environmental effects as migrating populations from an area with high occurrence of historical streptococcal epidemics (Europe) and low occurrence of streptococcal epidemics (West Africa) have kept their high and low prevalence rates (respectively) of psoriasis.

The very close correlation observed between historical mortality from systemic streptococcal infections and psoriasis prevalence could be coincidental. However, the alternative explanation is that part of the psoriasis genotype leads to a change in response to systemic streptococcal infection which then results in a reduced mortality. One could argue that other infections beside streptococci, such as smallpox and measles, could have had selection pressures that equally affected psoriasis prevalence.[21] However, streptococcal infection stands alone among these in being by far the commonest infective trigger for psoriasis, suggesting, perhaps, a special evolutionary relationship.

Guttate Psoriasis, Scarlet Fever and Superantigens: A Common Pathway?

In 1990 scarlet fever toxins (now known as streptococcal pyrogenic exotoxins, SPEs) were characterized as belonging to a group of secreted microbial proteins which act as superantigens.[22] These toxins were known to be a major mediator of scarlet fever as antiserum to these proteins abrogates the disease. Superantigens bind directly to MHC class II molecules and stimulate T cells through the V beta region alone activating up to 20% of naïve T cells, compared with only one in 105-106 of those responsive to conventional peptide antigen.[23] A streptococcal sore throat with subsequent superantigen immune stimulation can lead to extremely high amounts of cytokine secretion, particularly tumour necrosis factor (TNF)-α.[24] Massive proinflammatory cytokine production could lead to reduced vascular tone, resulting in widespread organ hypoperfusion, acidosis and multiorgan failure. Streptococcal superantigens upregulate the cutaneous lymphocyte-associated antigen (CLA) on T cells, facilitating their skin-homing capacity.[25,26] Thus the cutaneous features of scarlet fever, such as the exanthematous and oedematous rash and exfoliation of the upper layer of the skin, are a response to the massive cytokine release and activated T-cell infiltration.

Guttate psoriasis is characterized by the development of small psoriasis skin lesions commonly 2 weeks after a throat infection. The rash will often then stay for several weeks before either resolving or progressing to chronic plaque psoriasis. There is strong evidence that streptococcal infection, usually of the throat, is the prime cause of the initiation of guttate psoriasis. In one study, streptococci were isolated from the throat of 97% of patients with guttate psoriasis,[27] while in two earlier studies serological evidence of recent streptococcal infection was found in 56%[28] and 85%[29] of patients, respectively. Streptococcal superantigens appear to play a direct role in the pathogenesis of guttate psoriasis. In one study peripheral blood as well as lesional skin biopsies from patients with guttate psoriasis were analysed for T-cell receptor V beta expression.[30] Skin biopsies from all patients with acute guttate psoriasis, but not skin biopsies from control patients with other inflammatory diseases, demonstrated expansion of V beta 2+ T cells, with extensive junctional diversity compatible with a superantigen rather than a conventional antigen-driven T-cell response. All streptococcal isolates from the throats of the patients with guttate psoriasis secreted SPE C, known to stimulate marked V beta 2+ T-cell expansion. Another group showed peripheral blood expansion of V beta 2+ T cells which were also CLA positive (skin homing) in guttate psoriasis.[31]

Thus superantigen-driven T-cell activation occurs in both guttate psoriasis and the rash associated with scarlet fever/invasive streptococcal infection. Once activated T cells infiltrate the skin, however, the pathogenic pathways diverge, with keratinocyte death and exfoliation in scarlet fever compared with keratinocyte hyperproliferation in guttate psoriasis.