京都大学 / 新制・課程博士 / 博士(医学) / 甲第23790号 / 医博第4836号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 佐藤 俊哉, 教授 柳田 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects at least five million people worldwide. An increased expression of type I interferon (IFN) regulated genes is a hallmark of SLE, but the precise etiology of SLE initiation and flares is poorly understood. Because plasmacytoid dendritic cells (pDCs) are the primary type I IFN producers, their role in SLE has long been suspected, with murine pDC depletion models successfully delaying the progression of murine lupus-like disease. However, the mechanism behind how exactly how pDCs contribute to lupus autoimmunity is unknown, contributing to the current dearth lack of disease modifying treatments; current treatments only succeed in suppressing symptoms, and do not halt disease progression. In this study, we take a multifactorial approach to understanding the biology of pDCs in the context of lupus autoimmunity. Although the exact etiology of lupus is unknown, infections are an important environmental trigger for / Infectious Disease & Immunity

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24994号 / 医博第5028号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 上野 英樹, 教授 椛島 健治, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. The crosstalk between the gut microbiota and the immune system plays an important role in the tolerance induction to self-antigens both in the intestinal mucosa and at the systemic level. The MRL/lpr mouse model exhibits lupus-like symptoms early in life due to multiple SLE susceptible loci of the MRL background, plus the Faslpr mutation that offers an accelerated model. Recently, we experienced a loss of disease phenotype in our in-house colony compared to the previous published phenotype of MRL/lpr mice. We thus compared mice newly obtained from The Jackson Laboratory (JAX) with our in-house MRL/lpr mice and found that the phenotypic drift, most significantly the attenuation of glomerulonephritis, was present in both colonies. In addition, while JAX mice and mice in our colony are genetically identical, there were minor differences in disease that might be due to differences in splenic microRNAs and the gut microbiota. Once confirming that our MRL/lpr mouse model was as good as that from JAX, we continued our investigation of the role of Lactobacilli in the pathogenesis of lupus-like disease in MRL/lpr mice. We previously published that the mixture of Lactobacillus reuteri (L. reuteri), L. oris, L. johnsonii, L. gasseri, and L. rhamnosus significantly attenuated disease in MRL/lpr mice by restoring the imbalance between regulatory T cells and T helper-17 cells. To further understand the role of Lactobacillus spp., we treated MRL/lpr mice with the combined culture supernatant of the 5 strains containing secreted metabolites, given that the metabolites may induce an immunosuppressive response. The results showed significant attenuation of the inflammation of the spleen and renal lymph nodes similar to the effect of the bacteria themselves. There was also a trending decrease of double-stranded DNA autoantibodies with the combined supernatant. We thus tested the strains individually but none was able to recapitulate the effect of the bacterial mixture. This suggests cell-to-cell contact among different strains of lactobacilli may be required in ameliorating the disease. With these results, we now have a better understanding of the role of probiotic Lactobacillus spp. against SLE. Future investigations will focus on the potential therapeutic effect of Lactobacillus spp. as a combination. Additionally, our group generated a Cx3cr1-deficient MRL/lpr mouse which exhibits a distinct phenotype of exacerbated glomerulonephritis with concurrent change of the gut microbiota composition compared to Cx3cr1+/+ MRL/lpr littermates. Interestingly, upon correction of the gut microbiota with Lactobacillus administration, the phenotype of exacerbated glomerulonephritis was reversed, suggesting that CX3CR1 controls glomerulonephritis in MRL/lpr mice through a gut microbiota-dependent mechanism. In addition, a collaborative project revealed that Cx3cr1 deficiency-mediated pathogenic mechanisms also contributed to SLE-associated cardiovascular disease in MRL/lpr mice. The results of these studies will lead to the identification of new therapeutic targets for the treatment of two severe manifestations, glomerulonephritis and cardiovascular disease, that together account for most of the morbidity and mortality in SLE. / Doctor of Philosophy / Systemic lupus erythematosus (SLE) is an autoimmune disease with no known cure. Commensal microbiota, mostly bacteria living in our gut, and the immune system have a strong relationship in maintaining a healthy state of the gut as well as the whole body. Alterations in the gut microbiota, known as dysbiosis, can facilitate SLE in human and animal models. Current treatments for SLE are primarily focused on using immunosuppressants, but the side effects are still a concern. The use of long-term nonselective immunosuppressant conducts a higher incidence of severe infections in SLE patients. It is thus necessary to develop new approaches and treatments against SLE. My dissertation research is focused on understanding how commensal bacteria influence in the pathogenesis of SLE. My studies have shown that environmental factors can manipulate the gut microbiota leading to different disease outcomes. In addition, following upon previously published studies from our laboratory, I have delineated the mechanism how a mixture of probiotic Lactobacilli can exert a beneficial effect against lupus. Finally, I have revealed a new, CX3CR1-mediated mechanism through which the gut microbiota controls kidney disease in the MRL/lpr lupus-prone mouse model.

Systemic lupus erythematosus (SLE) is a chronic multifactorial inflammatory autoimmune disease with heterogeneous clinical manifestations. Among different manifestations, lupus nephritis (LN) remains a major cause of morbidity and mortality. There are few FDA approved treatments for LN. In general, they are non-selective and lead to global immunosuppression with significant side effects including an increased risk of infection. In the past 60 years, only one new drug, belimumab was approved for lupus disease with modest efficacy in clinic and not approved for patients suffering for nephritis. Therefore, it is urgent to develop new treatments to replace or reduce the use of current ones. Histone deacetylase 6 (HDAC6) plays a variety of biologic functions in a number of important molecular pathways in diverse immune cells. Both innate and adaptive immune cells contribute to pathogenesis of lupus. Among those cells, B cells play a central role in pathogenesis of lupus nephritis in an anti-body dependent manner through differentiation into plasma cells (PCs). As a result, HDAC6 inhibitors represent an entirely new class of agents that could have potent effects in SLE. Importantly, the available toxicity profile suggests that HDAC6 inhibitors could be advanced into SLE safely. We have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. ACY-738 is a hydroxamic acid HDAC6 inhibitor that is highly selective for HDAC6. In our current studies, we tested if an orally selective HDAC6 inhibitor, ACY-738, would decrease disease pathogenesis in a lupus mouse model with established early disease. Moreover, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. In order to define the mechanism by which HDAC6 inhibition decreases disease pathogenesis in NZB/W mice by using RNAseq to evaluate the transcriptomic signatures of splenocytes from treated and untreated mice coupled with applied computational cellular and pathway analysis. In addition, we sought to bridge between the transcriptomic data obtained from the HDAC6 treated mice and human gene expression information to determine the relevance to this target in possibly controlling human lupus. We treated 20-week-old (early-disease) NZB/W F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 4~5 weeks. As the mice aged, we determined autoantibody production and cytokine levels by ELISA, and renal function by measuring proteinuria. At the termination of the study, we performed a comprehensive analysis on B cells, T cells, and innate immune cells using flow cytometry and examined renal tissue for immune-mediated pathogenesis using immunohistochemistry and immunofluorescence. We then used RNAseq to determine the genomic signatures of splenocytes from treated and untreated mice and applied computational cellular and pathway analysis to reveal multiple signaling events associated with B cell activation and differentiation in SLE that were modulated by HDAC6 inhibition. Our results showed a reduced germinal center B cell response, decreased T follicular helper cells and diminished interferon (IFN)-γ production from T helper cells in splenic tissue. Additionally, we found the IFN-α-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. The molecular pathways by which B cells become pathogenic PC secreting autoantibodies in SLE are incompletely characterized. RNA sequence data showed that PC development was abrogated and germinal center (GC) formation was greatly reduced. When the HDAC6 inhibitor-treated lupus mouse gene signatures were compared to human lupus patient gene signatures, the results showed numerous immune and inflammatory pathways increased in active human lupus were significantly decreased in the HDAC6 inhibitor treated animals. Pathway analysis suggested alterations in cellular metabolism might contribute to the normalization of lupus mouse spleen genomic signatures, and this was confirmed by direct measurement of the impact of the HDAC6 inhibitor on metabolic activities of murine spleen cells. Taken together, these studies show selective HDAC6 inhibition decreased several parameters of disease pathogenesis in lupus-prone mice. The decrease was in part due to inhibition of B cell development and response. RNA sequence data analysis show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggests that a critical event might be modulation of cellular metabolism. / Doctor of Philosophy / Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease by which immune cells mistakenly attacks healthy self-cells in different organs. Kidney inflammation occurs in nearly 50% of patients with lupus resulting in kidney damage leading to end stage renal disease. Lupus nephritis (LN) is major cause of morbidity and mortality associated with SLE. Current treatments for LN consist primarily of immunosuppressants that block the immune response and leave the patients with unwanted side effects including an increased risk of infection. To circumvent the unwanted side effects, we explored a novel mechanism to target the immune response. My project was to determine whether histone deacetylase 6 (HDAC6) inhibition would suppress the autoimmune inflammatory response in lupus. We found that inhibition of HDAC6 was effective at attenuating early LN, probably by down-regulating innate immune response, which suppressed subsequent adaptive immune responses downstream. HDAC6 inhibition affected the innate immune response by inhibiting type I interferon production by plasmacytoid dendritic cells. HDAC6 inhibition affected the cell mediated immune response by decreasing T helper cell and B cell activation. To determine the mechanism by which HDAC6 inhibits immune cells activation, we used RNAseq to reveal HDAC6 inhibition on multiple signaling events associated with the induction of lupus disease. These results suggest that HDAC6 could be a potential therapeutic target in the early stage of LN.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving the inflammatory damages of multiple organs. Lupus nephritis (LN) as the manifestation in the kidney occurs in more than 50% of SLE patients and is a major cause of morbidity and mortality. Current treatments consist of immunosuppressants that always lead to compromised immune responses with increased risks of infections as the major side effect. To minimize this side effect, it is crucial to develop new treatments that are more natural and specific. Vitamin A, particularly in the form of its functional metabolite, retinoic acid, has shown some beneficial effects against LN in both lupus-prone mouse models and clinical cases. However, a more systemic evaluation of vitamin A treatment in lupus had not been investigated. In our study, we found paradoxical effects of all-trans-retinoic acid (tRA) on lupus-like disease in MRL/lpr lupus-prone mice. Starting at 6 weeks old when the inflammatory environment had been established in MRL/lpr mice, tRA administration reduced immune cell numbers in the secondary lymphoid organs and improved glomerulonephritis. However, circulating autoantibodies and inflammation in renal tubulointerstitium and other organs were increased. The detrimental effects of tRA were not present in MRL control mice, which didn't have an established inflammatory environment at 6 weeks old as shown in MRL/lpr mice, suggesting that the pro-inflammatory effects of tRA are dependent on the pre-existing inflammatory environment. Therefore, to successfully apply vitamin A-based treatment, it is important to avoid the detrimental effects of tRA on lupus by identifying and then specifically eliminating the critical pro-inflammatory immune cell types in lupus. As treatments usually start after the onset of apparent symptoms in patients at the effector stage of autoimmune responses, targeting the inflammatory contributors at this stage appears to be more practical and critical. Among different types of leukocytes, we chose to focus on dendritic cells (DCs), because they are highly diverse and critical in the immune responses as a bridge between the innate and adaptive immune systems. Plasmacytoid DCs (pDCs) as a candidate target have been demonstrated to be crucial for the initiation of lupus development by producing IFNα. However, we demonstrated that although pDCs produced a large amount of IFNα during disease initiation, those from late-stage lupus mice were found to be defective in producing IFNα, suggesting that pDC-targeted treatments should be performed at the initiation stage. This will depend on the progress in early diagnosis in the future. Besides pDCs, we identified a CD11c+ cell population absent at the early-stage but gradually accumulating at the late-stage in the kidneys of lupus mice. These cells have a phenotype of mature monocyte-derived DCs, with particularly high CX3CR1 expression on the surface. Consistent with their pathogenic cytokine profile, in vivo administration of anti-CX3CR1-saporin conjugates to dysfunction these cells in MRL/lpr mice significantly reduced proteinuria scores. Ex vivo activation of renal-infiltrating CD4+ T cells showed increased survival rate, proliferation and IFN-γ production of activated CD4+ T cells when they were cultured with these renal-infiltrating CD11c+ cells. These results suggest that the renal-infiltrating CD11c+ cells are pathogenic and promote inflammation in the kidney at the later effector stage of lupus by interacting with renal-infiltrating CD4+ T cells. In conclusion, although vitamin A showed anti-inflammatory effects on reducing glomerulonephritis, its use in lupus treatment should be guarded due to the other potential pro-inflammatory effects induced by the pre-existing inflammatory environment. IFNα-producing pDCs and CX3CR1highCD11c+ monocyte-derived DCs could be specific therapeutic targets to reduce the established inflammation at the early stage and late stage of LN, respectively. Therefore, it is worthwhile to further investigate the comprehensive effects of combination therapy on lupus, with vitamin A administration and pDCs-specific depletion at the early stage, and CX3CR1highCD11c+ monocyte-derived DCs-specific depletion at the late stage. / Ph. D.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. Despite years of study, the etiology of SLE is still unclear. Both genetic and environmental factors have been implicated in the disease mechanisms. Gut microbiota as an environmental factor and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of SLE is unclear. In a classical model of lupus nephritis, MRL/lpr, we found decrease of Lactobacillales but increase of Lachnospiraceae in the gut microbiota. Increasing Lactobacillales in the gut by suppling a mixture of 5 Lactobacillus strains improved renal function of these mice and prolonged their survival. Further studies revealed that MRL/lpr mice possessed a "leaky" gut, which was reversed by increased Lactobacillus colonization. Inside the kidney, oral Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. To remove Lachnospiraceae that was higher in lupus-prone mice than controls, we administered vancomycin orally to MRL/lpr mice after disease onset from 9 to 15 weeks of age. Vancomycin functions by removing Gram-positive bacteria such as Lachnospiraceae but sparing Lactobacillus spp. The treatment during active lupus reshaped the gut microbiota and significantly ameliorated systemic autoimmunity and kidney histopathology at 15 weeks of age. However, when vancomycin treatment was initiated from a very early age, the beneficial effect was not observed. Strikingly, mice given vancomycin only at the young age exhibited an even worse disease outcome. Indeed, regulatory B (Breg) cells were found to be reduced after the vancomycin treatment at young age. Importantly, adoptive transfer of Breg cells at 6-7 weeks of age rescued the beneficial effect, which indicates that Breg cells, inducible by vancomycin-sensitive gut microbiota, plays an important role in suppressing lupus disease initiation and progression. Finally, we demonstrated that bacterial DNA from the gut microbiota might be the inducer of Breg cells, as bacterial DNA administration at young age reproduced the beneficial effect seen in the Breg adoptive transfer experiment. Future studies are required to examine the clinical efficacy of targeting gut microbiota as a novel treatment against SLE. / Ph. D.

New Zealand Black/White F₁ hybrid (NZB/W) and MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop a Systemic Lupus Erythematosus-like autoimmune disease. While the primary immunologic defect in the NZB/W is due to B cells, in the MRL/lpr it is a result of T cell abnormalities. Diethyldithiocarbamate (DTC), an agent suggested to enhance T cell function, was used to treat both strains. Weekly treatment of NZB/W mice with 25 mg/kg DTC had no significant effect upon survival or autoantibody levels but did induce changes in cell surface antigen expression. MRL/lpr mice treated with DTC displayed normalization of cell surface antigen expression (particularly increased expression of Lyt-2, macrophage markers and Lyt-2⁺/L3T4⁺ thymocytes), decreased lymphoproliferation and thymic atrophy, decreased serum autoantibody levels and kidney deposition of C3 and IgM, restored responses to mitogens and significantly prolonged survival. To determine both the influence of MRL background and lpr genes and to better understand on what cell populations DTC effects, changes in cell surface antigen expression were examined in DTC treated MRL-+/+, Balb/c, and Balb/lpr strains. The only consistent similarities observed between all strains tested were DTC induced changes in Mac-1 splenocyte surface antigen expression. In vitro studies showed DTC to have variable effects upon the mitogenic responses of lymphoid cells to phytohemagluttinin, but DTC alone stimulated both MRL/lpr and Balb/lpr lymphocytes. DTC stimulated the null cell population that predominates in lpr gene-bearing mice, but all observed in vitro effects of DTC were dependent upon the adherent cell population included in culture. DTC had no apparent direct effects upon adherent cells alone however. These studies have shown that DTC is capable of positive effects upon one autoimmune murine strain, the MRL/lpr, but not the NZB/W. DTC appears to affect macrophages, but other cell populations are required to obtain full activity of this compound. The variable effects of DTC emphasize the need to define the immunopathology of individual patients with autoimmune disease before initiating treatment with immunomodulative therapy.

Les récepteurs Toll-like (TLRs) détectent des structures conservées exprimées par différentes classes de microorganismes, jouant ainsi un rôle majeur dans la réponse immunitaire. Les TLRs localisés dans les endosomes (TLR3, 7, 8 et 9) reconnaissent principalement des acides nucléiques dérivés de microbes. Cependant, ils peuvent également être responsables de la reconnaissance d’acides nucléiques endogènes et contribuer au développement d’auto immunité. A la différence du TLR8humain, le TLR8 murin n’induit pas de réponse à l’ARN simple brin et a ainsi été considéré comme non fonctionnel. Le but de cette étude est d’étudier le rôle du TLR8 murin dans l’immunité. Nous avons montré que les cellules dendritiques déficientes en TLR8 surexpriment le TLR7 et présentent une réponse accrue à une stimulation de TLR7. Chez la souris, la déficience en TLR8 entraine une augmentation des taux d’anticorps circulant (IgM, IgG, IgG2a), des autoanticorps, et au niveau rénal la présence de dépôts de complexes immuns. A l’inverse des souris TLR8-/-, les souris TLR7/8-/- sont protégées de tout symptôme. Nos résultats indiquent donc que chez la souris le TLR8 joue un rôle primordial dans la modulation de l’expression de TLR7, et cette régulation est cruciale dans le contrôle du développement d’autoimmunité spontanée. / Toll-like receptors (TLRs) detect conserved molecular products of microorganisms and play anessential role in the induction of immune responses. Endosomal TLRs (TLR3, 7, 8 and 9) sensenucleic acids derived from microbes. However they can also recognize self nucleic acids and thus beinvolved in the development of autoimmunity. Unlike human TLR8, murin TLR8 does not respond tosingle-stranded RNA suggesting that it could be not functional. In the current study, we investigatedthe role of murine TLR8 signaling in immunity. We found that TLR8-/- dendritic cells overexpressTLR7 and are hyperesponsive to various TLR7 ligands. In mice, TLR8 deficiency leads to increasedlevels of IgM, IgG, IgG2a circulating antibodies, autoantibodies and in the kidney to higher depositionof immunocomplexes while double TLR7/8-/- mice are protected from autoimmune features. Thesedata provide evidence for a pivotal role of murine TLR8 in the regulation of murine TLR7 expressionand this control is critical for the prevention of spontaneous autoimmunity development.

Objetivo: Avaliar a antropometria do pênis em pacientes com lúpus eritematoso sistêmico (LES) e controles. A possível influência da puberdade e dos fatores clínicos, hormonais e terapêuticos nas mediadas penianas em pacientes lúpicos. Métodos: Vinte e cinco pacientes consecutivos com LES foram avaliados através de exame urológico, ultrassonografia testicular com Doppler, dosagem hormonal [folículo estimulante (FSH), hormônio luteinizante (LH), prolactina, dosagem total de testosterona pela manhã e inibina B] e análise genética (síndrome Klinefelter e microdeleção do cromossomo Y). Comprimento do pênis foi medido como a distância linear ao longo do lado dorsal do pênis que se estende desde a junção da pele pubopeniana à ponta da glande no estado flácido, enquanto que a circunferência do pênis foi medida no ponto médio do eixo. As características clínicas, SLEDAI, SLICC / ACR-DI, e tratamento também foram avaliados. O grupo controle incluiu 25 homens de idade comparável e saudáveis. Resultados: Pacientes com LES tiveram o comprimento médio do pênis e da sua circunferência significantemente menor, em comparação aos controles [8 (7,5-10) vs. 10 (8-13) cm, p=0,0001; 8 (7-10) vs. 10 cm (11/07) , p=0,001; respectivamente], e mediana do volume testicular direito e esquerdo por Prader [15 (10-25) vs. 20 (12-25) cm, p=0,003; 15 (25/10) vs. 20 (12-25) cm, p=0,006, respectivamente], maior mediana de FSH [5,8 (2,1- 25) vs. 3,3 (1,9-9) UI/l, p=0,002] e menores níveis de testosterona total, dosados pela manhã (28% versus 0%, p = 0,009 ) quando comparados aos controles. Apesar desses achados, a disfunção erétil não foi observada nos pacientes ou controles. Outras análises revelaram que a mediana da circunferência do pênis foi menor nos pacientes com LES que tiveram o início da doença antes da primeira ejaculação [7,8 (7-10) vs. 9,0 (7,5-10) cm, p=0,026] em comparação com aqueles que começaram a doença após a primeira ejaculação. Antropometria do pênis no lúpus não esteve relacionado aos baixos níveis de testosterona total (p=0,662), ao SLEDAI 4 (p=0,562), SLICC / ACR-DI 1 (p=0,478), nem a dose cumulativa de prednisona (p=0,789), ou ciclofosfamida endovenosa (p=0,754). Síndrome de Klinefelter (46XY/47XXY) foi diagnosticada em apenas um (4%) paciente com LES, e este apresentava diminuição do tamanho do pênis. Já a microdeleção do cromossomo Y esteve ausente em todos eles. Conclusões: Nós identificamos redução das dimensões do pênis em pacientes com LES sem efeito deletério na função erétil. A diminuição da circunferência do pênis esteve associada ao início da doença antes da espermarca. / Objective: The aim of this study was to evaluate penile anthropometry in systemic lupus erythematosus (SLE) patients compared with healthy controls and the possible relevant pubertal, clinical,hormonal and treatment factors that could influence penile dimensions. Methods: Twenty-five consecutive SLE patients were assessed by urological examination, sexual function, testicular ultrasound, hormones, sperm analysis, genetic analysis, clinical features and treatment. The control group included 25 age-matched healthy males. Results: SLE patients had a lower median penis length and circumference [8 (7.510) vs. 10 (813) cm, p=0.0001; 8 (710) vs. 10 (711) cm, p=0.001; respectively], lower median testicular volume by right and left Prader [15 (1025) vs. 20 (1225) ml, p=0.003; 15 (1025) vs. 20 (1225) ml, p=0.006; respectively], higher median of follicle-stimulating hormone [5.8 (2.125) vs. 3.3 (1.99) IU/l, p¼0.002] and lower morning total testosterone levels (28% vs. 0%, p¼0.009) compared with controls. In spite of that, erectile dysfunction was not observed in patients or controls. Analyses of lupus patients revealed that the median penis circumference was lower in patients with disease onset before first ejaculation compared with those with disease onset after first ejaculation [7.8 (710) vs. 9.0 (7.510) cm, p=0.026]. No differences were observed in the median penile anthropometry regarding sexual dysfunction (p=0.610), lower morning total testosterone levels (p=0.662), oligo/azoospermia (p=0.705), SLE Disease Activity Index 4 (p=0.562), Systemic Lupus International Collaborating Clinics/ACR Damage Index 1 (p=0.478), prednisone cumulative dose (p=0.789) and intravenous cyclophosphamide therapy (p=0.754). Klinefelter´s syndrome (46XY/47XXY) was diagnosed in one (4%) SLE patient with decreased penile size whereas Y-chromosomal microdeletions was absent in all of them. Conclusion: we have identified reduced penile dimensions in SLE patients with no deleterious effect in erectile function. Disease onset before first ejaculation seems to affect penis development in pre-pubertal lupus.