Jean-Pierre Allam

Chronic orchitis: a neglected cause of male infertility?

Infection and inflammation of the male reproductive tract are accepted as important aetiological factors of infertility. With regard to their impact on male reproductive function, orchitis and epididymo‐orchitis due to local or systemic infection as well as noninfectious aetiological factors are of particular concern. There is clinical and pathological evidence that chronic inflammatory conditions of the testes can disrupt spermatogenesis and irreversibly alter both sperm number and quality. In the majority of patients, however, diagnosis is hampered by an asymptomatic course of the disease and unspecific clinical signs. Hence, respective epidemiological data are scarce. On the other hand, systematic histopathological work‐up of testicular biopsies from infertile men indicates a high prevalence of inflammatory reactions. A characteristic pattern of inflammatory lesions with focal or multifocal, predominantly peritubular lymphocyte infiltration and concomitant damage of seminiferous tubules is seen in chronic orchitis of various origins. This supports the concept that induction of testicular inflammation is associated with a T‐cell‐mediated autoimmune response, i.e. disruption of the immune privilege. Moreover, despite the patchy distribution of the lesions, testicular volume and score counts for spermatogenesis may be significantly reduced. In conclusion, asymptomatic inflammatory reactions in the testis should not be neglected as an underlying cause or co‐factor of male infertility. However, definitive diagnosis of chronic asymptomatic orchitis still requires testicular biopsy and guidelines for the therapeutic management are not yet available.

The immune privilege of the oral mucosa

Despite high bacterial colonization and frequent allergen contact, acute inflammatory and allergic reactions are rarely seen in the oral mucosa. Therefore we assert that immune tolerance predominates at this site and antigen presenting cells, such as dendritic cells and different T cell subtypes, serve as key players in oral mucosal tolerance induction. In this article we describe the mechanisms that lead to tolerance induced in the oral mucosa and how they differ from tolerance induced in the lower gastrointestinal tract. Furthermore we discuss ways in which novel nonparenteral approaches for immune intervention, such as allergen-specific immunotherapy applied by way of the sublingual route, might be improved to target the tolerogenic properties of the sophisticated oral mucosal immune network.

Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy?

Background:  Sublingual immunotherapy (SLIT) represents an alternative to subcutaneous immunotherapy. While antigen‐presenting cells such as Langerhans cells (LCs) are thought to contribute to the effectiveness of SLIT, mast cells (MCs) most likely account for adverse reactions such as sublingual edema. As little is known about LCs and MCs within the oral cavity, we investigated their distribution in search for mucosal sites with highest LCs and lowest MCs density.

Cellular and molecular immunologic mechanisms in patients with atopic dermatitis

Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.

Phl p 5 resorption in human oral mucosa leads to dose-dependent and time-dependent allergen binding by oral mucosal Langerhans cells, attenuates their maturation, and enhances their migratory and TGF-β1 and IL-10–producing properties

BACKGROUND Sublingual immunotherapy (SLIT) is safe and effective as treatment of allergic rhinitis and mild asthma. Oral mucosal Langerhans cells (oLCs) play a central role. However, little is known about allergen binding by oLCs during mucosal allergen resorption and its impact on oLC functions. OBJECTIVE Binding of Phl p 5 to oLCs was studied in a standardized ex vivo model to investigate mechanisms important for SLIT. METHODS Human oral mucosal biopsies were incubated with the grass pollen allergen Phl p 5. Migration, binding of Phl p 5, phenotype and cytokine production, and T-cell priming of Phl p 5-binding oLCs were analyzed. RESULTS Significant uptake required more than 5 minutes, and dose-dependent binding of Phl p 5 to oLCs was saturated at 100 microg/mL Phl p 5. Furthermore, Phl p 5 significantly increased the migratory capacity of oLCs but attenuated their maturation and strongly promoted the release of TGF-beta1 and IL-10 by oLCs themselves as well as by cocultured T cells. CONCLUSION Oral mucosal Langerhans cells bind Phlp5 in a dose-dependent and time-dependent manner, leading to an increased production of tolerogenic cytokines and an enhanced migratory capacity but decelerated maturation of oLCs.

Chronic epididymitis: impact on semen parameters and therapeutic options.

Chronic inflammatory conditions of the genital tract are frequently encountered in male fertility problems. The diagnosis, however, is hampered by a mostly asymptomatic course of the disease as well as inappropriate definitions and unspecific diagnostic criteria. With regard to their impact on male reproductive function, epididymitis seems to be more relevant than inflammation/infection of the prostate and/or seminal vesicles. Chronic epididymitis may result in reduced sperm count and motility. Impaired sperm motility because of epididymal dysfunction is frequently associated with an atypical staining behaviour of sperm tails. In many cases of chronic epididymitis, the number of leukocytes in the ejaculate is below the threshold of 106 per ml; therefore, consideration of additional markers of inflammation such as granulocyte elastase, pro‐inflammatory cytokines (e.g. interleukin‐6 or 8) or reactive oxygen species is helpful for establishing the diagnosis. Besides changes in the conventional sperm parameters, alterations in DNA integrity have been observed. Positive effects of antiphlogistic/antibiotic treatment on semen quality have been reported; however, controlled prospective studies are still lacking.

Comparative analysis of nasal and oral mucosa dendritic cells

Background:  Mucosal dendritic cells (DC) play a crucial role in tolerance induction as seen in mucosal immunotherapy of atopic diseases. Nevertheless little is known about the phenotypical differences of oral and nasal mucosal DC (nmDC). Recently, we could show that oral mucosal myeloid CD1a+ DC (omDC) differ from their skin counterparts especially by the expression of high affinity receptor for immunoglobulin E (IgE; FcɛRI). However, expression pattern of FcɛRI and phenotypical characteristics of CD1a+ nmDC have not been elucidated in detailed yet.

Immunological mechanisms of sublingual allergen-specific immunotherapy

To cite this article: Novak N, Bieber T, Allam J‐P. Immunological mechanisms of sublingual allergen‐specific immunotherapy. Allergy 2011; 66: 733–739.

The role of antigen presenting cells at distinct anatomic sites: they accelerate and they slow down allergies

It has been repeatedly demonstrated that allergic reactions are driven by the continuous flow of antigen uptake and presentation processes, which are perpetuated mainly by dendritic cells (DC). The ability of allergens to cause allergic inflammation is contingent upon the presence of an immunological milieu and microenvironment that either privileges Th2 responses or prohibits these reactions by the induction of contraregulatory anti‐inflammatory activities of the immune system. In the light of recent developments it appears that DC have to manage two opposing tasks: on the one hand they can favor pro‐inflammatory reactions and actively induce a T‐cell response, yet on the other hand they serve an important function as ‘silencers’ in the immune system by sending out anti‐inflammatory, tolerance inducing signals. This unique capacity of DC has opened several exciting possibilities for a role of DC in both – accelerating and slowing down allergic reactions. It is therefore a challenge to understand in which way DC subtypes located at distinct anatomic sites with frequent allergen exposure, such as the skin, the nasal mucosa, the respiratory tree or the mucosa of the intestinal tract can have an impact on mechanisms involved in tolerance induction or effective immunity.

Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

Much knowledge has been gained about the multifaceted functions of dendritic cells (DCs). The central role of various DC subtypes as bridges between innate and adaptive immunity has become more and more evident. However, a high number of differences exist in the expression of pattern-recognition receptors, the first sensors of the innate immune system, in particular Toll-like receptors (TLRs) by distinct DC subtypes (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, a plethora of variations in human and murine model systems have to be considered. This review sheds some light on this complex and rapidly growing field. It summarizes the most recent findings and deals with the role of TLR-expressing DCs as promoters of chronic inflammatory immune responses in patients with atopic dermatitis, as well as tolerogenic pathways. Therefore TLR-bearing DCs represent promising targets, which might help to improve tolerance induction during immunotherapeutic approaches in the future.