Unraveling the paradoxes of HIV-associated psoriasis: A review of T-cell subsets and cytokine profiles
Published Web Locationhttps://doi.org/10.5070/D34sf63339
Unraveling the paradoxes of HIV-associated psoriasis: A review of T-cell subsets and cytokine profiles1. UC Irvine Department of Dermatology2. UC Irvine School of Medicine 3. UC Irvine Department of Dermatology, Dermatology
Services, Long Beach VA Med Center. firstname.lastname@example.org 4. UCSF Department of Dermatology, Director, UCSF Psoriasis Day Care
Douglas J Fife MD1, Jeanette M Waller 2, Edward W Jeffes MD PhD3, John YM Koo MD4
Dermatology Online Journal 13 (2): 4
HIV-associated psoriasis appears paradoxical, being a T-cell mediated disease in the face of decreasing T-cell counts. Furthermore, psoriasis is generally mediated by type-1 cytokines, whereas in HIV, type-2 cytokines tend to predominate. How can one have psoriasis in the essentially Th2 environment of HIV? The details and pertinent research regarding T cell subsets and cytokine profiles in psoriasis, HIV, and HIV-associated psoriasis were reviewed. It appears that both in the presence and absence of HIV infection, psoriasis is largely mediated by memory CD8 T cells, and that IFN-γ secreted by these cells and others is of key importance. Studying psoriasis in a model such as HIV in which certain elements of the immune system are stripped away or altered may help us better understand the pathogenic mechanisms and potential treatment targets for psoriasis vulgaris.
A clear relationship exists between psoriasis and the profound immunosuppression of HIV infected patients. HIV-associated psoriasis occurs with a prevalence that is similar or increased compared to the general population (Table 1) [1, 2, 3, 4, 5]. Psoriasis often has its initial presentation in advanced HIV infection , and it may even be the initial clinical manifestation of HIV infection . Psoriasis tends to become more severe as the HIV infection progresses, and there is even some correlation between low CD4 counts and the severity of psoriasis [6, 7, 8].
Although common, HIV-associated psoriasis is poorly understood, likely because of two main paradoxes it presents: Firstly, although psoriasis worsens with dropping CD4 T-cell counts in HIV, therapies that decrease T-cell count cause psoriasis to improve [9, 10]. Secondly, HIV is typically characterized by a strong Th2 cytokine profile , whereas psoriasis vulgaris is characterized by a strong Th1 secretion pattern [12, 13, 14]. A closer look at the disposition of T cell subsets, cytokine profiles, and antigen presentation in HIV and psoriasis provides for better understanding and may clarify these apparent paradoxes.
This article discusses these paradoxes, as well as various theories for the worsening of psoriasis in HIV, including immune dysregulation, an increase in viral and bacterial antigens in the skin, genetic susceptibility, and direct effects of HIV proteins on keratinocytes.
T cells in psoriasis and HIV
T cells can be subdivided into many categories, such as CD4+ (helper/ suppressor) vs. CD8+ (cytotoxic), CD45RA+ (naïve) vs. CD45RO+ (memory), Th1 vs. Th2, and Tc1 vs. Tc2. The balance of these various cell types is significantly disrupted in HIV infection (Fig. 1). An evaluation of CD4+ and CD8+ naïve and memory T cell populations in HIV patients and HIV-negative psoriasis patients may help us to better understand the roles of these cells in HIV-associated psoriasis (Tables 2a, 2b).
Historically, CD4+ T cells were thought to be primarily responsible for driving the immune process leading to psoriasis, while CD8+ T cells were thought to have a suppressor role . In recent years, however, histologic, therapeutic, and genetic evidence have assigned the CD8+ lymphocyte a more prominent, even independent role in the pathogenesis of psoriasis vulgaris.
Histological evidence reveals that the accumulation of CD8+ memory lymphocytes in the epidermis is linked to both the onset and exacerbation of psoriasis . Multiple studies of psoriatic patients have shown that CD8+ T cell concentrations are increased in the epidermis and papillary dermis of lesional skin compared to uninvolved skin [15, 16, 17, 18, 19]. Analysis of lesional T cells has also demonstrated that the CD8 subpopulation expresses pro-inflammatory cytokines such as IFN-γ and TNF-α more frequently than the CD4 subpopulation [12, 14]. Among the CD8 cells, it is likely that the memory subset is most active in psoriasis; several studies, using both flow cytometry  and immunohistochemistry [18, 20], have demonstrated that the memory CD45RO+ T cells are overwhelmingly predominant in psoriatic lesions.
Furthermore, improvement of psoriasis lesions by various therapies including cyclosporine, PUVA, alefacept, and DAB389-IL2, and methotrexate is preceded by a decrease in epidermal T cells (primarily CD8+, CD45R0+) (Table 3) [6, 9, 10, 15, 21, 22, 23, 24, 25, 26, 27]. Genetically, the strong association of psoriasis with several MHC Class I antigens [6, 28, 29, 30, 31] provides additional support for the importance of CD8+ cytotoxic T cells in psoriasis (Table 4). Specifically in the setting of HIV, psoriasis has been strongly linked to MHC Class I antigens HLA-C602 [32, 33, 34] and HLA-B27 [30, 31, 35, 36]. Taken together, the above evidence supports a strong role of the CD8+ T cell, particularly the CD45R0+ memory subtype, in the pathogenesis of psoriasis.
At this point, a closer examination of the T-cell subtypes in HIV may help to provide greater understanding of HIV-associated psoriasis (Fig. 1). HIV progression is characterized by a decrease in the CD4+ T cell count, which leads to a decreased CD4/CD8 T cell ratio. In addition to this relative expansion of the CD8+ T cell population, one also sees either a constant or elevated absolute CD8+ T cell count in HIV patients [30, 37]. The CD8+ T cell count rises initially with HIV infection, and most studies find that a steady, elevated CD8+ cell count can be seen in the peripheral blood of HIV patients until very late in the disease, when CD4+ T cell counts are < 100 .
The HIV virus also affects the naïve and memory cell subpopulations differently depending on the T cell type (CD4+ vs. CD8+). The majority of studies show that the virus preferentially infects and replicates in CD45RO+ (memory/effector) CD4+ T cells; whereas in CD8+ T cells, it tends to "prefer" the CD45RA+ (naïve) subtype (Table 4) [29, 30, 31, 38, 39, 40, 41].
The HIV virus's effect on CD8 memory vs. naïve subpopulations is especially pertinent to our discussion of psoriasis. Recent evidence reveals that HIV can infect CD8+ T cells, presumably during a time in their immature state when they transiently express the CD4 molecule in addition to the CD8 molecule [38, 39, 42]. In contrast to what is seen in the CD4+ T cell population, HIV preferentially affects the CD45RA+ (naïve) CD8+ T cells [38, 39]. As the naïve CD45RA+, CD8+ T cell count decreases with HIV disease progression, it contributes to less of the total CD8+ T cell count. In advanced HIV, the memory CD8+ T cell subpopulation comprises over 85-90 percent of the total CD8+ T cell count, compared to 50 percent in healthy controls . And in HIV patients with CD4 count < 200, the memory CD8+ population comprises 80 percent of the total combined (CD4+ and CD8+) T cell count, compared to 15 percent in normal adults . The decrease in the naïve CD8+ subpopulation has been suggested as a possible explanation for the decreased ability of the patients to fight new infections while at the same time suffering from autoimmune diseases such as psoriasis [38, 39, 43, 44, 45, 46].
Some have also proposed that the imbalance of CD4/CD8 ratio itself may lead to immune dysregulation in HIV- associated psoriasis. One possible mechanism suggests that a subset of suppressor CD4+ T cells which normally have an inhibitory effect on the immunologic pathway leading to psoriasis, when depleted, can allow the pathway to proceed unchecked . This hypothesis is supported by an interesting case report of a healthy man with idiopathic CD4 lymphopenia with a long history of widespread psoriasis . Interestingly, his intralesional CD4 counts were similar to normal, healthy patients. Though only one case, it does support the notion of immune dysregulation as one possible mechanism for HIV-associated psoriasis.
Taken together, the expansion of the CD8+ memory T subset appears to be largely responsible for the paradoxical exacerbation of psoriasis in the immunocompromised state of HIV infection.
The opposing cytokine profiles of HIV and psoriasis
Cytokines produced by T cells are generally categorized into two types (Fig. 2a). Generally speaking, type 1 cytokines negatively regulate the production of type 2 cytokines, and vice versa. Psoriasis is typically recognized as being mediated by T cells that secrete type 1 cytokines [12-14, 48-50] whereas HIV is generally thought to cause a shift towards a Th2 cytokine profile [11, 51, 52].
The cytokine profile in psoriasis
Type 1 cytokines IFN-γ and TNF-α and their receptors are present in psoriatic epidermis , but absent or very low levels of type-2 cytokines such as IL-4 and IL-10 are found in psoriatic lesions [13, 50]. The paucity of plasma cells and B cells in psoriatic lesions also reflects the lack of type-2 cytokines in the lesions of these patients (Table 6) [44, 52]. When T cells extracted from psoriatic lesions are examined by mRNA PCR, they also show a trend toward type 1 cytokine production . Immunohistochemical , flow cytometric, and cell culture  analysis of T-cells from psoriatic skin [12, 14] also reveal a strong type 1 predominance.
Treatment of psoriasis results in a decreased expression of type 1 cytokines by both peripheral blood and lesional T-cells that correlates with clearing of the lesions, as shown in studies of UVB light therapy , fumarate therapy , and alefacept . The importance of type-1 cytokines in promoting the psoriatic phenotype is further evidenced by the improvement in psoriatic lesions when type-2 cytokines IL-10 [57, 58] and IL-4  are administered to patients to downregulate type-1 cytokines IFN-γ and TNF-α. Of the type 1 cytokines, significant evidence suggests IFN-γ as the key contributor to keratinocyte hyperproliferation in psoriasis [13, 26, 60, 61].
The cytokine profile in HIV infection
Clerici and Shearer were the first to apply the model of type 1 and type 2 cytokines to HIV infection in humans. In 1993 and 1994 they presented evidence that peripheral blood T cells from HIV patients have an increased production of the type-2 cytokines IL-4-6 and IL-10 [51, 62]. They also showed decreased production of Type-1 cytokines IL-2 and IFN-γ as the HIV infection progressed. They suggested that the switch from type 1 cytokine production to type 2 cytokine production was indicative of overall prognosis; those patients with higher type-1 responses leading to cell-mediated immunity had significantly lower rates of seroconversion and, for those infected, a slower progression towards AIDS. Multiple subsequent studies confirmed a decrease in IL-2 and stable or increasing levels of IL-4, IL-5, and IL-10 in the peripheral blood of HIV-infected individuals [11, 63, 64].
Downstream products of Th2 stimulation provide further evidence of the tendency toward a type 2 cytokine production in HIV. Because type-2 cytokines promote humoral immunity, one would expect to see elevated plasma cell levels and hypergamma-globulinemia in HIV patients; this hypothesis has been confirmed in several studies [11, 44, 65]. Correspondingly, this cytokine shift further compromises cell medicated immunity, paralleling the increase in intracellular opportunistic infections that occur with HIV progression [4, 8].
Although many consider the type 1 to type 2 cytokine shift to be a key feature in the progression of HIV [1, 52, 62], the exacerbation and occurrence of type-1 cytokine-mediated diseases such as psoriasis implies that cytokine profiles in HIV should not be oversimplified.
Although it has been repeatedly demonstrated that IL-2 production decreases and IL-4 and IL-10 production increases, there may not be a true or complete Th1-Th2 shift in HIV infection. Particularly with respect to IFN-γ, an important type 1 cytokine, several authors have shown an increase in production in HIV-infected individuals, particularly when examining CD8+ memory cells [11, 64, 65, 66, 67]. Some have proposed that while there may be a true Th1 to Th2 cytokine profile shift within the CD4 population, there may be an increased subpopulation of activated CD8+ T cells resulting in increased IFN-γ .
Others suggest that the cytokine shift is actually an effect of the differential disposition of memory and naïve T-cell subsets in HIV, as naïve subsets produce primarily IL-2, while the memory subsets produce IL-4, IL-10, and IFN-γ. Thus the expanded population of memory CD8+ cells produces higher levels of IL-4, IL-10, and IFN-γ, whereas the decreased IL-2 may be explained by the depletion of naïve subsets .
Thus, the notion of a complete Th1 to Th2 cytokine shift in HIV may be an oversimplification. The decrease in IL2 and increases in IL4, IL10, and constant or elevated IFN-γ suggests a unique cytokine pattern in HIV, which does not fit neatly into the Th1 vs. Th2 classification scheme (Table 6).
In summary, psoriasis in healthy individuals has been described as being mediated by type-1 cytokines, notably IFN-γ and TNF-α, with low levels of type-2 cytokines IL4 and IL10. HIV is traditionally thought to involve a shift from type 1 to type 2 cytokine profile with decreased IL2 and increased IL4 and IL10. Critical to understanding of psoriasis in HIV patients, however, is the fact that activated CD8+ cells produce increased levels of IFN-γ compared to healthy controls [30, 66, 68, 69]. Furthermore, because other type 1 cytokines are reduced in HIV, IFN-γ becomes a more likely candidate key factor driving the psoriatic phenotype.
PART 3. HLA-DR: A link between IFN-γ and Psoriasis, especially in HIV?
HLA-DR, an MHC class-II antigen, is generally found on antigen presenting cells of the immune system, such as B lymphocytes and monocytes. When expressed on T lymphocytes it is essentially a marker of activation [14, 70]. In normal human epidermis, HLA-DR expression is limited to Langerhans cells and acrosyringial epithelium . During inflammation, however, its expression can be induced in cells that normally have little to do with immune function. Most notably, skin lesions from over 38 dermatoses, all associated with dermal lymphocytic infiltrates, have been reported to contain HLA-DR+ keratinocytes . Psoriasis is included in this category of diseases; it is postulated that in actively inflamed psoriatic lesions, keratinocytes are induced by IFN-γ to synthesize and express HLA-DR . Injection of IFN-γ into normal, non-psoriatic human keratinocytes as well as into lesional skin has been shown to induce HLA-DR expression by keratinocytes . Furthermore, keratinocytes of non-lesional skin in normal psoriatic patients are not exposed to increased levels of IFN-γ and do not express HLA-DR .
It is thought that the keratinocyte expression of HLA-DR in promotes the further accumulation of leukocytes within psoriatic plaque [76, 77, 78]. A number of effective therapies for psoriasis, including fumaric acid therapy, cyclosporine, corticosteroids, methotrexate, anthralin, retinoids, and PUVA result both in growth inhibition of hyperproliferative cells and in the down regulation of keratinocytic HLA-DR expression. Many suspect that this down regulation of aberrant HLA-DR expression may itself play a key role in the mechanism of effectiveness of these treatments [23, 79].
A plausible role for keratinocyte HLA-DR expression in the pathogenesis of psoriasis could involve interaction with microbial superantigens . Exacerbation of psoriasis in normal patients is strongly associated with bacterial infection, especially by staphylococcal and streptococcal bacteria. Streptococcal pyrogenic exotoxins and staphylococcal enterotoxins can act as superantigens, thereby potently and polyclonally stimulating TCR VB+, CD4+ T cells and macrophages via binding to their MHC Class II molecules [81, 82, 83]. Superantigens have also been shown both in vitro and in vivo to stimulate production of TNF-α in HLA-DR+ human keratinocytes, even in the absence of T-cells [80, 84-86]. Furthermore, testing with a TSST-1 superantigen mutant specifically incapable of binding HLA-DR failed to induce lesions, indicating that the superantigens interacted directly with HLA-DR on the keratinocytes .
The above information provides a very plausible explanation for the worsening of psoriasis in HIV patients, regardless of the paucity of CD4+ T cells (Fig. 3). Specifically, HIV patients have high circulating levels of IFN-γ secondary to disease-induced expansion of the memory CD8+ population. Particularly in the setting of HIV, IFN-γ induces human keratinocytes to aberrantly express HLA-DR [75, 87]. Because HIV patients are susceptible to infection by streptococcus and staphylococcus, in addition to many other usual and opportunistic pathogens, they may be exposed to these and other superantigens chronically or at high levels . Accordingly, many have shown that infections with staphylococcus or streptococcus are closely linked to increases in psoriatic flares of HIV positive patients [7, 6, 35 , 43, 88, 80, 90, 91, 92, 93].
Interestingly, it was recently proposed that the HIV virus's own gp120 envelope protein itself acts as a superantigen, capable of stimulating B cells, CD4+ T cells, and basophils [94, 95, 96]. Whether gp120 is capable of stimulating HLA-DR+ keratinocytes in the manner that other superantigens do has apparently not been studied to date. However, if gp120 can indeed act as a superantigen to stimulate HLA-DR+ keratinocytes, this could provide a likely mechanism for the HIV virus itself inducing psoriasis in previously non-psoriatic patients.
Other possible mechanisms for HIV-induced psoriasis
Some have proposed that the presence of the HIV virus itself in skin keratinocytes and Langerhans cells of HIV patients [96, 97] may play a more direct role. It has been postulated that HIV tat gene, or other portions of the HIV genome, may directly stimulate epidermal and endothelial proliferation [28, 31]. This is supported by transgenic mice studies in which mice containing intact copies of proviral HIV DNA produced a clinical and histological phenotype similar to psoriasis skin lesions , the finding of proviral DNA in dermal dendritic and Langerhans cells [98, 99], and in the improvement of psoriasis with antiretroviral therapy [5, 43, 92, 99, 100, 101, 102].
Namazi et al. have suggested that HIV-induced nitric oxide production by macrophages, increased release of Substance P in the skin of HIV-infected individuals, and reduction of the Langerhans' cells in the skin of HIV patients may be other factors in HIV-associated psoriasis .
One finding that seems to confound the above discussion is the multiple reports of psoriasis improving in the late stages of AIDS [30, 35, 103]. If the virus itself were responsible, we would expect psoriasis to worsen late in the course. This finding, however, does not eliminate the possibility of HIV acting as a costimulatory factor through antigenic presentation.
The exacerbation of psoriasis in the setting of HIV forces us to reevaluate our understanding of the immune processes active in its pathogenesis. Careful analysis reveals that psoriasis is largely mediated by CD45RO+, memory CD8+ T cells, the same population of cells that is both relatively and absolutely expanded in HIV infection. Although psoriasis is characterized by the type 1 cytokines IL2, TNF-α, and IFN-γ, with the latter predominating, IFN-γ produced by CD8+ T cells in HIV may also be the main perpetrator of psoriasis in that setting.
The mechanistic connection between IFN-γ and psoriasis in HIV is uncertain, although is possible that IFN-γ induces keratinocytes to aberrantly express HLA-DR, thus predisposing the keratinocytes to polyclonal activation by superantigens and typical antigens, likely in excess in the setting of HIV. Once activated, these keratinocytes produce TNF-α and other cytokines that perpetuate the psoriatic phenotype. Furthermore, the findings of the HIV virus itself in skin cells of infected individuals implies numerous possibilities for an alternative or additional, more direct role of the virus in inducing psoriatic flares.
Studying psoriasis in the setting of HIV may help to clarify the basic pathogenic mechanisms of psoriasis vulgaris, assigning prominent roles to CD8+ memory T cells and IFN-γ in the pathogenesis of both HIV-associated psoriasis and psoriasis vulgaris. This information may be of great clinical importance in an era where specific targeting of disease mediators is possible.
References1. Wolfer LU, Djemadji-Oudjiel N, Hiletework M, Tebbe B, Husak R, Goerdt S, Orfanos CE. HIV-associated psoriasis. Clinical and histological observations in 36 patients. Hautarzt. 1998 Mar;49(3):197-202. PubMed.
2. Garbe C, Husak R, Orfanos CE. HIV-associated dermatoses and their prevalence in 456 HIV-infected patients. Relation to immune status and its importance as a diagnostic marker. Hautarzt. 1994 Sep;45(9):623-9. PubMed
3. Berman A, Espinoza LR, Diaz JD, Aguilar JL, Rolando T, Vasey FB, Germain BF, Lockey RF. Rheumatic manifestations of human immunodeficiency virus infection. Am J Med. 1988 Jul; 85(1):59-64. PubMed.
4. Munoz-Perez MA, Rodriguez-Pichardo A, Camacho F, Colmenero MA. Dermatological findings correlated with CD4 lymphocyte counts in a prospective 3 year study of 1161 patients with human immunodeficiency virus disease predominantly acquired through intravenous drug abuse. Br J Dermatol. 1998 Jul;139(1):33-9. PubMed
5. Kaplan MH, Sadick NS, Wieder J, Farber BF, Neidt GW. Antipsoriatic effects of zidovudine in human immunodeficiency virus-associated psoriasis. J Am Acad Dermatol. 1989 Jan;20(1):76-82. PubMed
6. Badger J, Berger TG, Gambla C, Koo JY. HIV and psoriasis. Clin Rev Allergy Immunol. 1996-1997 Winter;14(4):417-31. PubMed
7. Obuch ML, Maurer TA, Becker B, Berger TG. Psoriasis and human immunodeficiency virus infection. J Am Acad Dermatol. 1992 Nov;27(5 Pt 1):667-73. PubMed
8. Myskowski PL, Ahkami R. Dermatologic complications of HIV infection. Med Clin North Am. 1996 Nov;80(6):1415-35. PubMed
9. Ortonne JP, Lebwohl M, Em Griffiths C; Alefacept Clinical Study Group. Alefacept-induced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic plaque psoriasis. Eur J Dermatol. 2003 Mar-Apr;13(2):117-23. PubMed
10. Ellis CN, Krueger GG; Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001 Jul 26;345(4):248-55. PubMed
11. Klein SA, Dobmeyer JM, Dobmeyer TS, Pape M, Ottmann OG, Helm EB, Hoelzer D, Rossol R. Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry. AIDS. 1997 Jul 15;11(9):1111-8. PubMed
12. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol. 1999 Nov;113(5):752-9. PubMed
13. Szabo SK, Hammerberg C, Yoshida Y, Bata-Csorgo Z, Cooper KD. Identification and quantitation of interferon-gamma producing T cells in psoriatic lesions: localization to both CD4+ and CD8+ subsets. J Invest Dermatol. 1998 Dec;111(6):1072-8. PubMed
14. Friedrich M, Krammig S, Henze M, Docke WD, Sterry W, Asadullah K. Flow cytometric characterization of lesional T cells in psoriasis: intracellular cytokine and surface antigen expression indicates an activated, memory/effector type 1 immunophenotype. Arch Dermatol Res. 2000 Oct;292(10):519-21. PubMed
15. Baker BS, Griffiths CE, Lambert S, Powles AV, Leonard JN, Valdimarsson H, Fry L. The effects of cyclosporin A on T lymphocyte and dendritic cell sub-populations in psoriasis. Br J Dermatol. 1987 Apr;116(4):503-10. PubMed
16. Cameron AL, Kirby B, Fei W, Griffiths CE. Natural killer and natural killer-T cells in psoriasis. Arch Dermatol Res. 2002 Nov;294(8):363-9. PubMed
17. Austin LM, Coven TR, Bhardwaj N, Steinman R, Krueger JG. Intraepidermal lymphocytes in psoriatic lesions are activated GMP-17(TIA-1)+CD8+CD3+ CTLs as determined by phenotypic analysis. J Cutan Pathol. 1998 Feb;25(2):79-88. PubMed
18. Vissers WH, Arndtz CH, Muys L, Van Erp PE, de Jong EM, van de Kerkhof PC. Memory effector (CD45RO+) and cytotoxic (CD8+) T cells appear early in the margin zone of spreading psoriatic lesions in contrast to cells expressing natural killer receptors, which appear late. Br J Dermatol. 2004 May;150(5):852-9. PubMed
19. Namazi MR. Paradoxical exacerbation of psoriasis in AIDS: proposed explanations including the potential roles of substance P and gram-negative bacteria. Autoimmunity. 2004 Feb;37(1):67-71. PubMed
20. Ichihashi N, Seishima M, Takahashi T, Muto Y, Kitajima Y. A case of AIDS manifesting pruritic papular eruptions and psoriasiform lesions: an immunohistochemical study of the lesional dermal infiltrates. J Dermatol. 1995 Jun;22(6):428-33. PubMed 21. Baker BS, Powles AV, Savage CR, McFadden JP, Valdimarsson H, Fry L. Intralesional cyclosporin in psoriasis: effects on T lymphocyte and dendritic cell subpopulations. Br J Dermatol. 1989 Feb;120(2):207-13. PubMed
22. Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, Krueger JG. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med. 1995 May;1(5):442-7. PubMed
23. Vallat VP, Gilleaudeau P, Battat L, Wolfe J, Nabeya R, Heftler N, Hodak E, Gottlieb AB, Krueger JG. PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J Exp Med. 1994 Jul 1;180(1):283-96. PubMed
24. Weinstein GD, Jeffes E, McCullough JL. Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol. 1990 Nov;95(5):49S-52S. PubMed
25. Baker BS, Swain AF, Griffiths CE, Leonard JN, Fry L, Valdimarsson H. Epidermal T lymphocytes and dendritic cells in chronic plaque psoriasis: the effects of PUVA treatment. Clin Exp Immunol. 1985 Sep;61(3):526-34. PubMed
26. Bata-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD. Intralesional T-lymphocyte activation as a mediator of psoriatic epidermal hyperplasia. Invest Dermatol. 1995 Jul;105(1 Suppl):89S-94S. PubMed
27. Krueger GG, Ellis CN. Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol. 2003 Apr;148(4):784-8. PubMed
28. Mallon E, Bunker CB. HIV-associated psoriasis. AIDS Patient Care STDS. 2000 May;14(5):239-46. PubMed
29. Henseler T. The genetics of psoriasis. J Am Acad Dermatol. 1997 Aug;37(2 Pt 3):S1-11. PubMed
30. Duvic M. Immunology of AIDS related to psoriasis. J Invest Dermatol. 1990 Nov;95(5):38S-40S. PubMed
31. Arnett FC, Reveille JD, Duvic M. Psoriasis and psoriatic arthritis associated with human immunodeficiency virus infection. Rheum Dis Clin North Am. 1991 Feb;17(1):59-78. PubMed
32. Mallon E, Young D, Bunce M, Gotch FM, Easterbrook PJ, Newson R, Bunker CB. HLA-Cw*0602 and HIV-associated psoriasis. Br J Dermatol. 1998 Sep;139(3):527-33. PubMed
33. Gonzalez S, Martinez-Borra J, Del Rio JS, Santos-Juanes J, Lopez-Vazquez A, Blanco-Gelaz M, Lopez-Larrea C. The OTF3 gene polymorphism confers susceptibility to psoriasis independent of the association of HLA-Cw*0602. J Invest Dermatol. 2000 Nov;115(5):824-8. PubMed
34. Mallon E, Bunce M, Wojnarowska F, Welsh K. HLA-CW*0602 is a susceptibility factor in type I psoriasis, and evidence Ala-73 is increased in male type I psoriatics. J Invest Dermatol. 1997 Aug;109(2):183-6. PubMed
35. Duvic M, Johnson TM, Rapini RP, Freese T, Brewton G, Rios A. Acquired immunodeficiency syndrome-associated psoriasis and Reiter's syndrome. Arch Dermatol. 1987 Dec;123(12):1622-32. PubMed
36. Reveille JD, Conant MA, Duvic M. Human immunodeficiency virus-associated psoriasis, psoriatic arthritis, and Reiter's syndrome: a disease continuum? Arthritis Rheum. 1990 Oct;33(10):1574-8. PubMed
37. Gruber R, Endl J, Froschl M, Rieber EP, Ziegler-Heitbrock HW, Riethmuller G. Quantitative analysis of CD6, CD4 and CD8 cell surface molecules compared to the absolute numbers of CD6+, CD4+ and CD8+ T-cells in peripheral blood in patients with HIV-infection. J Clin Lab Immunol. 1991 Aug;35(4):157-63. PubMed
38. Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA, Herzenberg LA. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest. 1995 May;95(5):2061-6. PubMed
39. McBreen S, Imlach S, Shirafuji T, Scott GR, Leen C, Bell JE, Simmonds P. Infection of the CD45RA+ (naive) subset of peripheral CD8+ lymphocytes by human immunodeficiency virus type 1 in vivo. J Virol. 2001 May;75(9):4091-102. PubMed
40. Sleasman JW, Aleixo LF, Morton A, Skoda-Smith S, Goodenow MM. CD4+ memory T cells are the predominant population of HIV-1-infected lymphocytes in neonates and children. AIDS. 1996 Nov;10(13):1477-84. PubMed
41. Spina CA, Prince HE, Richman DD. Preferential replication of HIV-1 in the CD45RO memory cell subset of primary CD4 lymphocytes in vitro. J Clin Invest. 1997 Apr 1;99(7):1774-85. PubMed
42. Imlach S, McBreen S, Shirafuji T, Leen C, Bell JE, Simmonds P. Activated peripheral CD8 lymphocytes express CD4 in vivo and are targets for infection by human immunodeficiency virus type 1. J Virol. 2001 Dec;75(23):11555-64. PubMed
43. Fischer T, Schworer H, Vente C, Reich K, Ramadori G. Clinical improvement of HIV-associated psoriasis parallels a reduction of HIV viral load induced by effective antiretroviral therapy. AIDS. 1999 Apr 1;13(5):628-9. PubMed
44. Horn TD, Herzberg GZ, Hood AF. Characterization of the dermal infiltrate in human immunodeficiency virus-infected patients with psoriasis. Arch Dermatol. 1990 Nov;126(11):1462-5. PubMed
45. Reveille JD. The changing spectrum of rheumatic disease in human immunodeficiency virus infection. Semin Arthritis Rheum. 2000 Dec;30(3):147-66. PubMed
46. Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev. 2002 Dec;1(6):329-37. PubMed
47. Hardman CM, Baker BS, Lortan J, Breuer J, Surentheran T, Powles A, Fry L. Active psoriasis and profound CD4+ lymphocytopenia. Br J Dermatol. 1997 Jun;136(6):930-2. PubMed
48. Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, Meyer zum Buschenfelde KH, Fleischer B. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol. 1994 Feb;102(2):145-9. PubMed
49. Szegedi A, Aleksza M, Gonda A, Irinyi B, Sipka S, Hunyadi J, Antal-Szalmas P. Elevated rate of Thelper1 (T(H)1) lymphocytes and serum IFN-gamma levels in psoriatic patients. Immunol Lett. 2003 May 1;86(3):277-80. PubMed
50. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993 Nov;101(5):701-5. PubMed
51. Clerici M, Shearer GM. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107-11. PubMed
52. Bos JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH. Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal antibodies. Arch Dermatol Res. 1983;275(3):181-9. PubMed
53. Vollmer S, Menssen A, Trommler P, Schendel D, Prinz JC. T lymphocytes derived from skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that is distinct from that of T helper type 1 and T helper type 2 cells. Eur J Immunol. 1994 Oct;24(10):2377-82. PubMed
54. Piskin G, Koomen CW, Picavet D, Bos JD, Teunissen MB. Ultraviolet-B irradiation decreases IFN-gamma and increases IL-4 expression in psoriatic lesional skin in situ and in cultured dermal T cells derived from these lesions. Exp Dermatol. 2003 Apr;12(2):172-80. PubMed
55. Litjens NH, Nibbering PH, Barrois AJ, Zomerdijk TP, Van Den Oudenrijn AC, Noz KC, Rademaker M, Van De Meide PH, Van Dissel JT, Thio B. Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines. Br J Dermatol. 2003 Mar;148(3):444-51. PubMed
56. Kobayashi S, Sugiyama H, Gyulai R. Alefacept treatment for psoriasis reduced the number of infiltrating IFNg+ -producing T cells in lesional skin. J Invest Dermatol 2001; 117: 546.
57. Reich K, Garbe C, Blaschke V, Maurer C, Middel P, Westphal G, Lippert U, Neumann C. Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation. J Invest Dermatol. 2001 Feb;116(2):319-29. PubMed
58. Friedrich M, Docke WD, Klein A, Philipp S, Volk HD, Sterry W, Asadullah K. Immunomodulation by interleukin-10 therapy decreases the incidence of relapse and prolongs the relapse-free interval in Psoriasis. J Invest Dermatol. 2002 Apr;118(4):672-7. PubMed
59. Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, van der Zee R, Biedermann T, Prinz J, Mack M, Mrowietz U, Christophers E, Schlondorff D, Plewig G, Sander CA, Rocken M. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med. 2003 Jan;9(1):40-6. PubMed
60. Prinz JC, Gross B, Vollmer S, Trommler P, Strobel I, Meurer M, Plewig G. T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol. 1994 Mar;24(3):593-8. PubMed
61. Ovigne JM, Baker BS, Brown DW, Powles AV, Fry L. Epidermal CD8+ T cells in chronic plaque psoriasis are Tc1 cells producing heterogeneous levels of interferon-gamma. Exp Dermatol. 2001 Jun;10(3):168-74. PubMed
62. Clerici M, Shearer GM. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575-81. PubMed
63. Tanaka M, Hirabayashi Y, Gatanaga H, Aizawa S, Hachiya A, Takahashi Y, Tashiro E, Kohsaka T, Oyamada M, Ida S, Oka S. Reduction in interleukin-2-producing cells but not Th1 to Th2 shift in moderate and advanced stages of human immunodeficiency virus type-1-infection: direct analysis of intracellular cytokine concentrations in CD4+ CD8- T cells. Scand J Immunol. 1999 Nov;50(5):550-4. PubMed
64. Graziosi C, Pantaleo G, Gantt KR, Fortin JP, Demarest JF, Cohen OJ, Sekaly RP, Fauci AS. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994 Jul 8;265(5169):248-52. PubMed
65. Barcellini W, Rizzardi GP, Borghi MO, Fain C, Lazzarin A, Meroni PL. TH1 and TH2 cytokine production by peripheral blood mononuclear cells from HIV-infected patients. AIDS. 1994 Jun;8(6):757-62. PubMed
66. Fuchs D, Hausen A, Reibnegger G, Werner ER, Dierich MP, Wachter H. Psoriasis, gamma-interferon, and the acquired immunodeficiency syndrome. Ann Intern Med. 1987 Jan;106(1):165. PubMed
67. Caruso A, Licenziati S, Canaris AD, Cantalamessa A, Corulli M, Benzoni B, Peroni L, Balsari A, Turano A. Characterization of T cell subsets involved in the production of IFN-gamma in asymptomatic HIV-infected patients. AIDS Res Hum Retroviruses. 1996 Jan 20;12(2):135-41. PubMed
68. Breuer-McHam JN, Marshall GD, Lewis DE, Duvic M. Distinct serum cytokines in AIDS-related skin diseases.Viral Immunol. 1998;11(4):215-20. PubMed
69. Breuer-McHam JN, Ledbetter LS, Sarris AH, Duvic M. Cytokine expression patterns distinguish HIV associated skin diseases. Exp Dermatol. 2000 Oct;9(5):341-50. PubMed
70. McBroom RL, Styles AR, Chiu MJ, Clegg C, Cockerell CJ, Radolf JD. Secondary syphilis in persons infected with and not infected with HIV-1: a comparative immunohistologic study. Am J Dermatopathol. 1999 Oct;21(5):432-41. PubMed
71. Murphy GF, Shepard RS, Harrist TJ, Bronstein BR, Bhan AK. Ultrastructural documentation of HLA-DR antigen reactivity in normal human acrosyringial epithelium. J Invest Dermatol. 1983 Aug;81(2):181-3. PubMed
72. Aubock J, Romani N, Grubauer G, Fritsch P. HLA-DR expression on keratinocytes is a common feature of diseased skin. Br J Dermatol. 1986 Apr;114(4):465-72. PubMed
73. Terui T, Aiba S, Kato T, Tanaka T, Tagami H. HLA-DR antigen expression on keratinocytes in highly inflamed parts of psoriatic lesions. Br J Dermatol. 1987 Jan;116(1):87-93. PubMed
74. Baker BS, Powles AV, Valdimarsson H, Fry L. An altered response by psoriatic keratinocytes to gamma interferon. Scand J Immunol. 1988 Dec;28(6):735-40. PubMed
75. Sebok B, Bonnekoh B, Vetter R, Schneider I, Gollnick H, Mahrle G. The antipsoriatic dimethyl-fumarate suppresses interferon-gamma -induced ICAM-1 and HLA-DR expression on hyperproliferative keratinocytes. Quantification by a culture plate-directed APAAP-ELISA technique. Eur J Dermatol. 1998 Jan-Feb;8(1):29-32. PubMed
76. Griffiths CE, Voorhees JJ, Nickoloff BJ. Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor. J Am Acad Dermatol. 1989 Apr;20(4):617-29. PubMed
77. Nickoloff BJ. Role of interferon-gamma in cutaneous trafficking of lymphocytes with emphasis on molecular and cellular adhesion events. Arch Dermatol. 1988 Dec;124(12):1835-43. PubMed
78. Barker JN, MacDonald DM. Cutaneous lymphocyte trafficking in the inflammatory dermatoses. Br J Dermatol. 1992 Mar;126(3):211-5. PubMed
79. Gottlieb AB. Immunologic mechanisms in psoriasis. J Am Acad Dermatol. 1988 Jun;18(6):1376-80. PubMed
80. Travers JB, Hamid QA, Norris DA, Kuhn C, Giorno RC, Schlievert PM, Farmer ER, Leung DY. Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis. J Clin Invest. 1999 Nov;104(9):1181-9. PubMed
81. Kappler J, Kotzin B, Herron L, Gelfand EW, Bigler RD, Boylston A, Carrel S, Posnett DN, Choi Y, Marrack P. V beta-specific stimulation of human T cells by staphylococcal toxins. Science. 1989 May 19;244(4906):811-3. PubMed
82. Choi YW, Kotzin B, Herron L, Callahan J, Marrack P, Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941-5. PubMed
83. Kotzin BL, Leung DY, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv Immunol. 1993;54:99-166. PubMed
84. Nickoloff BJ, Mitra RS, Green J, Zheng XG, Shimizu Y, Thompson C, Turka LA. Accessory cell function of keratinocytes for superantigens. Dependence on lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. J Immunol. 1993 Mar 15;150(6):2148-59. PubMed
85. Tokura Y, Yagi J, O'Malley M, Lewis JM, Takigawa M, Edelson RL, Tigelaar RE. Superantigenic staphylococcal exotoxins induce T-cell proliferation in the presence of Langerhans cells or class II-bearing keratinocytes and stimulate keratinocytes to produce T-cell-activating cytokines. J Invest Dermatol. 1994 Jan;102(1):31-8. PubMed
86. Ezepchuk YV, Leung DY, Middleton MH, Bina P, Reiser R, Norris DA. Staphylococcal toxins and protein A differentially induce cytotoxicity and release of tumor necrosis factor-alpha from human keratinocytes. J Invest Dermatol. 1996 Oct;107(4):603-9. PubMed
87. Langford A, Kunze R, Lobeck H, Pohle HD, Reichart P. Distribution of cytokeratins in oral cytological smears of HIV-infected patients. J Oral Pathol Med. 1992 Feb;21(2):58-64. PubMed
88. Leung DY, Travers JB, Giorno R, Norris DA, Skinner R, Aelion J, Kazemi LV, Kim MH, Trumble AE, Kotb M, et al. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest. 1995 Nov;96(5):2106-12. PubMed
89. Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens? Immunol Today. 1995 Mar;16(3):145-9. PubMed
90. Bos JD, De Rie MA. The pathogenesis of psoriasis: immunological facts and speculations. Immunol Today. 1999 Jan;20(1):40-6. PubMed
91. Prinz JC. Which T cells cause psoriasis? Clin Exp Dermatol. 1999 Jul;24(4):291-5. PubMed
92. Duvic M, Crane MM, Conant M, Mahoney SE, Reveille JD, Lehrman SN. Zidovudine improves psoriasis in human immunodeficiency virus-positive males. Arch Dermatol. 1994 Apr;130(4):447-51. PubMed
93. Lazar AP, Roenigk HH Jr. AIDS and psoriasis. Cutis. 1987 Apr;39(4):347-51. PubMed
94. Florio G, Petraroli A, Patella V, Triggiani M, Marone G. The immunoglobulin superantigen-binding site of HIV-1 gp120 activates human basophils. AIDS. 2000 May 26;14(8):931-8. PubMed
95. Torres BA, Perrin GQ, Mujtaba MG, Subramaniam PS, Anderson AK, Johnson HM. Superantigen enhancement of specific immunity: antibody production and signaling pathways. J Immunol. 2002 Sep 15;169(6):2907-14. PubMed
96. Mahoney SE, Duvic M, Nickoloff BJ, Minshall M, Smith LC, Griffiths CE, Paddock SW, Lewis DE. Human immunodeficiency virus (HIV) transcripts identified in HIV-related psoriasis and Kaposi's sarcoma lesions. J Clin Invest. 1991 Jul;88(1):174-85. PubMed
97. Compton CC, Kupper TS, Nadire KB. HIV-infected Langerhans cells constitute a significant proportion of the epidermal Langerhans cell population throughout the course of HIV disease. J Invest Dermatol. 1996 Dec;107(6):822-6. PubMed
98. Leonard JM, Abramczuk JW, Pezen DS, Rutledge R, Belcher JH, Hakim F, Shearer G, Lamperth L, Travis W, Fredrickson T, et al. Development of disease and virus recovery in transgenic mice containing HIV proviral DNA. Science. 1988 Dec 23;242(4886):1665-70. PubMed
99. Duvic M, Rios A, Brewton GW. Remission of AIDS-associated psoriasis with zidovudine. Lancet. 1987 Sep 12;2(8559):627. PubMed
100. Berthelot P, Guglielminotti C, Fresard A, Lucht F, Perrot JL. Dramatic cutaneous psoriasis improvement in a patient with the human immunodeficiency virus treated with 2',3'-dideoxy,3'-thyacytidine [correction of 2',3'-dideoxycytidine] and ritonavir. Arch Dermatol. 1997 Apr;133(4):531. PubMed
101. Diez F, del Hoyo M, Serrano S. Zidovudine treatment of psoriasis associated with acquired immunodeficiency syndrome. J Am Acad Dermatol. 1990 Jan;22(1):146-7. PubMed
102. Townsend BL, Cohen PR, Duvic M. Zidovudine for the treatment of HIV-negative patients with psoriasis: a pilot study. J Am Acad Dermatol. 1995 Jun;32(6):994-9. PubMed
103. Colebunders R, Blot K, Mertens V, Dockx P. Related Articles, Links Psoriasis regression in terminal AIDS. Lancet. 1992 May 2;339(8801):1110. PubMed
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