IgG4-Related Disease with Selective Testicular Involvement- A Rare Entity: Case Report with Review of Literature.

Immunoglobin-G4 related disease (IgG4-RD) is an auto-immune inflammatory condition where patients present with a tumour-like mass that shows infiltration by plasma cell and subsequent fibrosis. It is a systemic condition that primarily involves the salivary glands, pancreas, kidneys, aorta, and retroperitoneum amongst other organs. Testicular involvement is a rare occurrence in this disease entity. A 55-year old male patient presented with the complaints of pain and swelling in the right scrotal region. Right-sided orchidectomy was carried out which on histopathology showed features suggestive of IgG4-RD which was later confirmed on immunohistochemistry. Whole body MRI revealed that no other organ was involved in the disease process in this patient. IgG4-RD has a variable clinical course and considerable overlap with its differentials. Imaging studies and serum IgG4 levels are neither confirmatory nor customarily diagnostic in every case. The only confirmatory diagnostic investigation is histopathological examination, which shows infiltration of IgG4+ plasma cells and fibrosis in the involved tissue. Whenever a mass-forming lesion with typical histomorphological features is encountered with involvement of multiple organs/anatomic sites, IgG4-related disease should be considered among the differentials, and clinicians of all disciplines should be familiar with this disease entity.

Stromal cell-derived factor-1α predominantly mediates the ameliorative effect of linagliptin against cisplatin-induced testicular injury in adult male rats.

Stromal cell-derived factor-1α (SDF-1α) plays a key role in trafficking of stem cells and regeneration of injured tissue through interaction with its receptor, CXCR4. This study investigated the probable therapeutic effect of linagliptin (LG) against cisplatin (CP)-induced testicular injury and the underlying mechanisms. 12 week old male Sprague-Dawley rats were randomly assigned into 6 groups (n = 10 each) as follow: (i) Control, (ii) LG-treated control, (iii) CP-exposed rats, (iv) CP-exposed rats received LG, (v) CP-exposed rats received AMD3100, as CXCR4 antagonist, and (vi) CP-exposed rats received AMD3100 prior to LG. After 15 days, blood, testes and epididymides were collected for analyses. There were significant increases in both circulatory and testicular levels of SDF-1α in LG-treated rats. Conversely, higher levels of incretin hormones were found in serum but not in testicular tissue of rats, following LG therapy. CP injection significantly reduced body, testicular and epididymal weights of rats, and were restored by LG therapy. Treatment of CP-exposed rats with LG improved the deteriorated testicular architecture, reconstructed spermatogenesis, increased sperm count and quality, and normalized testosterone levels. LG therapy increased gene expression of Lin28a and Mvh, but did not alter the expressions of somatic-related genes. Additionally, LG therapy promoted germ cells survival and proliferation likely via activation of extracellular signal-regulated kinase1/2 (ERK1/2) signaling. These positive effects of LG therapy were almost blunted by administration of AMD3100. These results provided mechanistic insights into the ameliorative effect of LG on CP-induced testicular injury, through activation of SDF-1α/CXCR4 signaling pathway. Our findings suggest that LG can be a promising therapeutic candidate for CP-induced testicular injury.

Recombinant Chimpanzee Adenovirus Vaccine AdC7-M/E Protects against Zika Virus Infection and Testis Damage.

The recent outbreak of Zika virus (ZIKV) has emerged as a global health concern. ZIKV can persist in human semen and be transmitted by sexual contact, as well as by mosquitoes, as seen for classical arboviruses. We along with others have previously demonstrated that ZIKV infection leads to testis damage and infertility in mouse models. So far, no prophylactics or therapeutics are available; therefore, vaccine development is urgently demanded. Recombinant chimpanzee adenovirus has been explored as the preferred vaccine vector for many pathogens due to the low preexisting immunity against the vector among the human population. Here, we developed a ZIKV vaccine based on recombinant chimpanzee adenovirus type 7 (AdC7) expressing ZIKV M/E glycoproteins. A single vaccination of AdC7-M/E was sufficient to elicit potent neutralizing antibodies and protective immunity against ZIKV in both immunocompetent and immunodeficient mice. Moreover, vaccinated mice rapidly developed neutralizing antibody with high titers within 1 week postvaccination, and the elicited antiserum could cross-neutralize heterologous ZIKV strains. Additionally, ZIKV M- and E-specific T cell responses were robustly induced by AdC7-M/E. Moreover, one-dose inoculation of AdC7-M/E conferred mouse sterilizing immunity to eliminate viremia and viral burden in tissues against ZIKV challenge. Further investigations showed that vaccination with AdC7-M/E completely protected against ZIKV-induced testicular damage. These data demonstrate that AdC7-M/E is highly effective and represents a promising vaccine candidate for ZIKV control.IMPORTANCE Zika virus (ZIKV) is a pathogenic flavivirus that causes severe clinical consequences, including congenital malformations in fetuses and Guillain-Barré syndrome in adults. Vaccine development is a high priority for ZIKV control. In this study, to avoid preexisting anti-vector immunity in humans, a rare serotype chimpanzee adenovirus (AdC7) expressing the ZIKV M/E glycoproteins was used for ZIKV vaccine development. Impressively, AdC7-M/E exhibited exceptional performance as a ZIKV vaccine, as follows: (i) protective efficacy by a single vaccination, (ii) rapid development of a robust humoral response, (iii) durable immune responses, (iv) robust T cell responses, and (v) sterilizing immunity achieved by a single vaccination. These advantages of AdC7-M/E strongly support its potential application as a promising ZIKV vaccine in the clinic.

Changes in Gene Expression and Metabolism in the Testes of the Rat following Spinal Cord Injury.

Spinal cord injury (SCI) results in devastating changes to almost all aspects of a patient's life. In addition to a permanent loss of sensory and motor function, males also will frequently exhibit a profound loss of fertility through poorly understood mechanisms. We demonstrate that SCI causes measureable pathology in the testis both acutely (24 h) and chronically up to 1.5 years post-injury, leading to loss in sperm motility and viability. SCI has been shown in humans and rats to induce leukocytospermia, with the presence of inflammatory cytokines, anti-sperm antibodies, and reactive oxygen species found within the ejaculate. Using messenger RNA and metabolomic assessments, we describe molecular and cellular changes that occur within the testis of adult rats over an acute to chronic time period. From 24 h, 72 h, 28 days, and 90 days post-SCI, the testis reveal a distinct time course of pathological events. The testis show an acute drop in normal sexual organ processes, including testosterone production, and establishment of a pro-inflammatory environment. This is followed by a subacute initiation of an innate immune response and loss of cell cycle regulation, possibly due to apoptosis within the seminiferous tubules. At 1.5 years post-SCI, there is a chronic low level immune response as evidenced by an elevation in T cells. These data suggest that SCI elicits a wide range of pathological processes within the testes, the actions of which are not restricted to the acute phase of injury but rather extend chronically, potentially through the lifetime of the subject. The multiplicity of these pathological events suggest a single therapeutic intervention is unlikely to be successful.

IgG4-related disease of the paratestis in a patient with Wells syndrome: a case report.

BACKGROUND: We report a case of a 33-year-old man who presented with immunoglobulin (Ig)G4-related disease (IgG4-RD) forming a pseudotumor in the left paratesticular region during oral administration of corticosteroid for Wells syndrome, which involves cellulitis with eosinophilia. CASE PRESENTATION: The patient was introduced to our institution from a private hospital with a 3-month history of asymptomatic left scrotal mass. A 5-cm diameter nodule was palpable in the left scrotum. Tumor lesion in the left paratestis involving the epididymis and spermatic cord was observed on computed tomography and magnetic resonance imaging. Blood testing showed no abnormalities other than a minimal increase in C-reactive protein levels. Urine examination likewise revealed no significant findings. Left radical orchidectomy was performed under a diagnosis of left paratesticular neoplasm suspected as malignant tumor. The tumor was pathologically identified as IgG4-RD of the left paratestis involving the epididymis and spermatic cord. CONCLUSIONS: We present a first description of IgG4-RD in a patient with Wells syndrome and the ninth case of IgG4-RD in a scrotal organ, and discuss this very rare entity with reference to the literature. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_225.

The IGSF1 deficiency syndrome: characteristics of male and female patients.

CONTEXT: Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. OBJECTIVE: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. METHODS: All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. RESULTS: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. CONCLUSION: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Testicular microlithiasis is not a risk factor for the production of antisperm antibody in infertile males.

Testicular microlithiasis (TM) is a pathological event characterised by the presence of microliths within the testicular entities, and such calcium deposition is thought to have deleterious impacts on the structure of blood-testis barrier (BTB). Breaches in the BTB appear to be a risk factor for antisperm antibody (ASA) production, which is reported to have negative influence on human fertility. Thus, the theories are provocative that ASA formation is elicited in TM men, and the resultant ASA will accordingly affect the fecundity in these men. To illustrate these hypotheses, this study enrolled 22 infertile men incidentally diagnosed with TM by testicular ultrasound evaluation. Sperm samples were collected, and direct immunobead test was used to determine the ASA levels. None of the infertile men with TM were found to display significant levels of ASA, whilst relatively abnormal sperm parameters in these cases were revealed by semen analysis. These observations suggest that TM exposure does not increase the risk of ASA production in infertile men, and therefore, ASA is discarded as an active participant in the development of infertility in TM men. Nevertheless, disrupted spermatogenesis resulting from TM may, at least in part, have certain implications for the pathogenesis of TM-associated infertility.

Cadmium exposure increases susceptibility to testicular autoimmunity in mice.

Cadmium, one of various environmental toxicants, is known to suppress systemic immunity and to injure the testicular capillary endothelia with resultant necrosis of testicular tissues in mice and rats treated with high doses. Recently, it also became evident that cadmium can affect the integrity of the blood-testis barrier (BTB), the endocrine function of Leydig cells, apoptosis of germ cells and systemic immunity, even on treatment with a low dose that does not induce spermatogenic disturbance. Experimental autoimmune orchitis (EAO), i.e., an organ-specific autoimmunity of the testis, can be induced by repeated immunization with testicular antigens, and its pathology is characterized by lymphocytic inflammation and spermatogenic disturbance. In the present study, we investigated the morphological and functional changes of testes in mice treated with a low dose of cadmium chloride (CdCl2 ) and also examined its toxicity as to susceptibility to EAO. The results showed that exposure to 3 mg CdCl2 kg(-1) body weight did not affect the spermatogenic state. However, the BTB at the tubuli recti and the rete testis, but not the seminiferous tubules, was slightly weakened, and intra-testicular mRNA expression of interleukin (IL)-6, tumor necrosis factor-α and IL-1ß was significantly increased by the CdCl2 treatment. Furthermore, immunization with testicular antigens after the CdCl2 exposure significantly augmented the EAO severity. Therefore, exposure to a low dose of CdCl2 induces no significant disturbance of spermatogenesis, however, it does change the immunological microcircumstances in the testis, resulting in increased susceptibility to testicular autoimmunity.

IgG4-related paratesticular pseudotumor in a patient with autoimmune pancreatitis and retroperitoneal fibrosis: an extrapancreatic manifestation of IgG4-related disease.

In this report, we describe the first case of a patient with an IgG4-related paratesticular pseudotumor. He had histologically proven autoimmune pancreatitis, then later developed a scrotal mass. The orchiectomy specimen revealed that this was a paratesticular pseudotumor with histopathologic and immunohistochemistry findings characteristic of IgG4-related disease. Paratesticular pseudotumors are uncommon causes of intrascrotal masses and have an unexplained pathogenesis. A variety of genitourinary manifestations of IgG4-related disease including IgG4-related tubulointerstitial nephritis, IgG4-related ureteral pseudotumors, and IgG4-related prostatitis has been previously reported. The current case highlights the need to have a high index of suspicion for IgG4-tissue infiltration in patients with known autoimmune pancreatitis, particularly those with a pseudotumor.

Influence of inguinal hernia mesh repair on testicular flow and sperm autoimmunity.

BACKGROUND: The incidence of infertility caused by the mesh inguinal hernia repair is not known. The aim of this study was to determine circulation and immunological testicular disorders after inguinal hernia mesh repair which can be related with infertility. METHODS: From February 2010 to December 2010, 43 male patients who underwent inguinal hernia mesh repair were included in a prospective study. Testicular, capsular and intratesticular arterial flow dynamics were measured by Color Doppler ultrasound before the operation, in early and late postoperative period. The antisperm antibodies were analyzed before hernia repair and 5 months after. RESULTS: The difference between patients who underwent laparoscopic (Group I) and anterior open tension-free hernia repair (Group II) in age, duration of symptoms and hernia characteristics were not significant. Statistically significant differences were found in peak-systolic and end-diastolic velocity in testicular and intratesticular arteries in Group II and in peak-systolic velocity on all levels in Group I. Only Group I had significant differences in resistive index of intratesticular arteries. All the values returned to basal in late postoperative period except testicular peak-systolic velocity in Group I which stayed in normal range. Wilcox matched pair test showed significant difference between preoperative and late postoperative measurements of the antisperm antibodies only in Group II, but it was within normal range in all cases. CONCLUSIONS: Inguinal hernia mesh repair do not have clinically significant influence on testicular flow and immunological response.

The autoimmune bases of infertility and pregnancy loss.

Several lines of evidence suggest that autoimmune mechanisms may influence the reproductive life and fertility of both sexes, commonly manifesting as infertility or pregnancy loss. Part of the controversy that characterizes this assumption derives from the overlooked suspect of autoimmune conditions in the absence of symptoms or the limited physician awareness in a gynecological setting. Numerous autoimmune diseases, including but not limited to systemic lupus erythematosus and anti-phospholipid syndrome, may be associated with infertility and pregnancy loss through different putative mechanisms. First, serum autoantibodies such as anti-phospholipid, anti-thyroid, or antinuclear antibodies may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease. Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss. Third, infertility may also be secondary to vasculitis associated with other conditions such as systemic lupus erythematosus and diabetes mellitus. This review article will illustrate and critically discuss the available data on the link between the breakdown of tolerance that characterizes autoimmune diseases and the changes in reproductive life that affect patients in real clinical setting and that often constitute the iatrotropic stimulus.

[Flow cytometry application in the evaluation of antisperm antibodies in sera samples of infertile people and prepubertal boys with gonadal disorders]. / Wykorzystanie cytometrii przeplywowej do oceny wystepowania przeclwcial przeciwplemnikowych w surowicy od nieplodnych osób doroslych i chlopców przed pokwitaniem z wadami w drogachi rozrodczych.

OBJECTIVES: The aim of the following study was to assess antisperm antibodies in sera samples of infertile men and women, as well as from prepubertal boys by means of flow cytometry. MATERIAL AND METHODS: We tested sera samples of infertile and fertile adult populations, prepubertal boys with gonadal disorders and healthy prepubertal boys. The indirect immunobead test and flow cytometry were used to detect antisperm antibodies. RESULTS: The comparison of antisperm antibody levels in sera samples of adult infertile versus healthy controls (men and women) evaluated by means of flow cytometry did not reveal statistically significant differences. The only significant correlation found were results obtained by IDIBT and FCM for IgG antisperm antibodies for infertile adult group (r = 0.507, p = 0.012). The comparison of antisperm antibody levels in sera samples from prepubertal boys revealed statistically significant differences for all tested antibody isotypes. Diagnostic values compared for both assays showed markedly better discriminatory ability of flow cytometry for analyzed groups of prepubertal boys than for adult populations. CONCLUSIONS: Flow cytometry test may be used to verify antisperm antibody levels in prepubertal boys with testicular failures.

Antisperm antibodies detected by mixed agglutination reaction and immunobead test are not associated with chronic inflammation and infection of the seminal tract.

The association between chronic inflammatory/infectious diseases of the male reproductive tract and the presence of antisperm antibodies (ASA) in semen is still controversial. We compared the results of the mixed agglutinin reaction (MAR) test and immunobead test for detecting ASA type IgG and IgA in 133 patients attending our special outpatient department for andrological infections and evaluated the differences in the detection rate of ASA. Patients were divided into three groups: a study group that included 79 patients with symptomatic nonacute inflammatory/infectious diseases of the seminal tract, a control group (n = 44) and a third group of men with a history of successful vasectomy reversal (n = 10). The two tests correlated in a statistically significant manner for the detection of IgG and IgA in all groups. The overall positive detection rate of clinical significant levels of IgG and IgA was 2.5% and 1.3% (respectively) in the patients with inflammation/infection of the seminal tract. No statistical significant difference in the detection rate of ASA levels between the inflammatory/infectious group and the controls was detected. The results of the MAR test and immunobead test have a statistical significant correlation and their results provide evidence that there is no association between inflammatory/infectious diseases of the male reproductive tract and the presence of ASA in semen.

Relationship between time of reperfusion and E-selectin expression, neutrophil recruitment, and germ cell apoptosis after testicular ischemia in a rat model.

OBJECTIVE: To examine the relationship between the time of reperfusion and neutrophil recruitment, E-selectin expression, and germ cell apoptosis in the ischemic and contralateral testis after testicular ischemia-reperfusion (IR) injury in a rat. DESIGN: Laboratory study. SETTING: Research laboratory in a faculty of medicine at Technion-institute of technology in Israel. ANIMAL(S): Sixty adult Sprague-Dawley rats weighing 250-280 g. INTERVENTION(S): Testicular IR. MAIN OUTCOME MEASURE(S): Testicular germ cell apoptosis was assessed by terminal deoxynucleotide transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling immunohistochemical assay, using an in situ cell death detection kit. The recruitment of polymorphonuclear (PMN) cells was calculated per 100 venules. Expression of E-selectin was determined by using immunohistochemical analysis. RESULT(S): E-selectin expression and polymorphonuclear-cell recruitment in the contralateral testis increased significantly after 1 hour of reperfusion and then remained unchanged during the first 24-48 hours, followed by a gradual decrease. Germ cell apoptosis in the contralateral testis increased after 6 hours of reperfusion, achieved statistical significance after 24 hours, and decreased after 72 hours of reperfusion. CONCLUSION(S): Germ cell apoptosis in the contralateral testis increases most significantly within the first 24-48 hours, followed by a gradual decrease, after IR injury. E-selectin expression and neutrophil recruitment increases within the first 6 hours and apparently may initiate the increase in germ cell apoptosis.

Testicular ischemia due to intravascular large B-cell lymphoma: a novel presentation in an immunosuppressed individual.

A 56-year-old man presented with fever, disorientation, and testicular pain. He was receiving azathioprine immunosuppression for autoimmune hepatitis. Orchiectomy identified occlusion of spermatic cord vessels by intravascular large B-cell lymphoma (IVLBL) and ischemic changes in the testis. Tumor cells were positive for CD 10, CD 20, CD 30, and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) and early region RNA (EBER). He was treated with the cessation of azathioprine, chemotherapy, anti-CD 20 immunotherapy, and radiotherapy. Twenty months after diagnosis, he is alive with no evidence of lymphoma or hepatitis. This is the first report of IVLBL presenting with testicular ischemia. It highlights the importance of prompt diagnosis and intervention to achieve durable response. That this lymphoma arose in the setting of immunosuppressive therapy introduces additional complexity relating to pathogenesis, clinical behavior, and treatment.

Cyclophosphamide-immunodepressed FVB/N mice: potentiating the effects of testicular cytomegalovirus infection.

The aim of this study was to investigate the effect of cyclophosphamide (CY) immunosuppression on the infection of germinal cells following testicular inoculation of male FVB/N mice with murine cytomegalovirus (MCMV). We used CY to modulate the immune status in order to mimic iatrogenic immunosuppression in humans (organ transplantation) as closely as possible. We show that viral pathological manifestations observed in mice treated with this CY-MCMV combination were severer than those observed in immunocompetent male mice infected with MCMV alone. As previously reported, the typical MCMV cellular inclusions were present in interstitial spaces; however, the spermatogenic cells were never directly infected. Nonetheless, at the end of our observation, we obtained definitive necrosis of the testes. These results suggest that germline cell necrosis induces sterility in immunodepressed infected male mice indirectly. In the case of organ transplantation, particular attention should be accorded to male patients receiving CY.

Pro-inflammatory cytokine response of the fluid contents of spermatoceles and epididymal cysts.

The aim of the study was to determine the cellular contents and concentrations of interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in fluids of patients with spermatocele or epididymal cyst. Twenty-five symptomatic patients, 14 with epididymal cysts and 11 with spermatoceles, were included in the study. Fluids were obtained during surgical excision of the cysts and cytological smears were stained with May-Gruenwald-Giemsa to establish cell components. The concentrations of IL-6, IL-8 and TNF-alpha were measured by chemiluminescent immunometric assay. Cytological analysis of the fluids demonstrated various sperm forms ranging from immature germ cells to degenerated spermatozoa without inflammatory cells such as neutrophils and macrophages. The concentrations (mean+/- SEM, pg/mg protein) of IL-6, IL-8 and TNF-alpha were 13.52 +/- 1.40, 22.20 +/- 2.43, 3.51 +/- 1.43 in spermatocele fluids and 5.76 +/- 0.48, 11.57 +/- 1.89, 2.53 +/- 0.41 in epididymal cyst fluids. Both IL-6 and IL-8 concentrations in the spermatocele group were higher than in the epididymal cyst group (P < 0.0001). There were no differences in TNF-alpha concentrations between the groups (P > 0.05). These findings indicate that local production of pro-inflammatory cytokines is involved in cyst formation. The presence of immunologic activation in these fluids advocates a policy of selective surgical intervention in patients with spermatocele or epididymal cyst.

Possible role of autoimmunity to spermatozoa in idiopathic infertility of stallions.

Testicular degeneration is a major cause of subfertility in stallions, although an aetiological diagnosis cannot be made in most cases. In the present study, autoimmune testicular degeneration was induced and evaluated in stallions by immunizing stallions with their own spermatozoa mixed with an adjuvant. The factors evaluated included changes in semen quality and testicular histology. A large decrease in sperm number and quality was observed in response to sperm autoantigens. An ELISA test specific for antisperm antibodies was developed which enabled antibody titres in serum, seminal plasma and accessory sex organs to be measured. Serum antibodies were characterized as being specific for spermatozoa by absorption studies and western blotting. The data obtained and the tests developed in the present study provide a better understanding of the disease in subfertile breeding stallions and the ability to diagnose the disease using ELISA. The results of a clinical trial demonstrate that there is a higher incidence of antisperm antibodies in subfertile stallions compared with fertile stallions. The results of the present study indicate that autoimmunity to spermatozoa plays a role in idiopathic subfertility in stallions. A potentially useful method for tentative diagnosis of autoimmune testicular degeneration in subfertile stallions was also developed.

Major differences between the testis and epididymis in the induction of granulomas in response to extravasated germ cells. I. A light microscopical study in mice.

A spermatic granuloma is a chronic inflammatory lesion which surrounds extravasated spermatozoa. Clinically, the lesion develops in the interstitial spaces of the epididymis and vas deferens, and only exceptionally in the testis itself. In the present study, murine testes and epididymides were injured using a needle and the histological appearances of these organs was then compared. Traumatic injury induced extravasation of germ cells in both testes and epididymides. A few days later, spermatic granulomas consistently formed in the epididymides, however, such lesions were not induced in the testes. To examine the possibility that epididymal spermatozoa have inherently greater ability to form spermatic granulomas than do testicular germ cells, isolated epididymal spermatozoa or testicular germ cells were locally injected into the testes and epididymides of recipient mice. Spermatic granulomas readily formed in the epididymides after local injection of either epididymal spermatozoa or testicular germ cells. In contrast, such lesions did not form in the testes even when epididymal spermatozoa were injected. Therefore, this study suggests that the microenvironment of the testicular interstitium, rather than the extravasated components from the ruptured seminiferous tubules, is the main factor determining the limited formation of spermatic granulomas in the testis.