Development Of Granulomas Research Articles

Immune stimulation following dermal exposure to unsintered indium tin oxide

In recent years, several types of pulmonary pathology, including alveolar proteinosis, fibrosis, and emphysema, have been reported in workers in the indium industry. To date, there remains no clear understanding of the underlying mechanism(s). Pulmonary toxicity studies in rats and mice have demonstrated the development of mediastinal lymph node hyperplasia and granulomas of mediastinal lymph nodes and bronchus-associated lymphoid tissues following exposure to indium tin oxide. Given the association between exposure to other metals and the development of immune-mediated diseases, these studies were undertaken to begin to investigate the immuno-modulatory potential of unsintered indium tin oxide (uITO) in a mouse model. Using modifications of the local lymph node assay, BALB/c mice (five animals/group) were exposed topically via intact or breached skin or injected intradermally at the base of the ear pinnae with either vehicle or increasing concentrations 2.5–10% uITO (90:10 indium oxide/tin oxide, particle size <50 nm). Dose-responsive increases in lymphocyte proliferation were observed with a calculated EC3 of 4.7% for the intact skin study. Phenotypic analysis of draining lymph node cells following intradermal injection with 5% uITO yielded a profile consistent with a T-cell-mediated response. These studies demonstrate the potential for uITO to induce sensitization and using lymphocyte proliferation as a biomarker of exposure, and demonstrate the potential for uITO to penetrate both intact and breached skin.

Immunopathology of granulomas produced by Mycobacterium bovis in naturally infected wild boar

Limited information has been published on the wild boar immune response against bovine tuberculosis (bTB) and the immunopathogenesis of the pathological hallmark (granuloma) in this species.The main objectives of this study were, on the one hand, to characterize the histopathological features (number of acid-fast bacilli (AFB) and multinucleated giant cells (MNGCs) and the immunohistochemical distribution of different cell subsets (CD3+, CD79a+ and MAC387+) and chemical mediators (iNOS and IFN-γ) in the different developmental stages of granulomas produced by the natural infection of Mycobacterium bovis (M. bovis) in wild boar. On the other hand, the study also aimed to analyze the mechanisms underlying the marked differences in the typical lesional patterns observed in M. bovis infections of wild boar (contained, not generalized) and those previously described in fallow deer (poorly contained, generalized).The majority of granulomas analyzed (95.3%) did not show any AFB with the ZN stain and a low number of MNGCs were identified in the different granuloma stages. The immunohistochemical analysis showed that MAC387 was the only immune marker that produced decreasing positivity by granuloma stage, being statistically significantly lower in stages III and IV when compared to stage I and II. Immune markers for lymphocyte cells (CD3 and CD79a) showed a slight rise in the positivity (which was not statistically significant) in the advanced granuloma stages. In keeping with the presence of large numbers of T cells and macrophages, there was a consistently high level of expression of IFN-γ at all stages of granuloma development without a statistical significant decrease in advanced stages. Also related with the higher presence of macrophages in stage I and II, the expression of iNOS was higher in early stages and sustained until stage III, showing a non statistical significant decrease in stage IV. The macrophage and iNOS activity are more intense and sustained along the granuloma development than those described in fallow deer.Immunohistochemical protocols with a panel of markers for wild boar different cells subsets (CD3+, CD79a+ and MAC387+) and chemical mediators (iNOS and IFN-γ), and their use to further investigate the immune response in this species are provided.

In Vitro Study of Phenotypical Characteristics of BCG Granuloma Macrophages Over the Course of Granuloma Development

Structural and immunophenotypical characteristics of macrophages, associated with their polarization in the M1 and M2 directions of differentiation and activation, were studied in different morphological types of BCG granulomas by the expression of GM-CSF, IFN-γ, and FGFb cytokines and CD36 and CD16/32 differentiation clusters. The proportion of IFN-γ and FGFb macrophage subpopulations changed over the course of granuloma formation, which led to accumulation of FGFb macrophages in the granulomas. These data indicated that the formation of macrophage granulomas and their subsequent transformation into epithelioid-cell granulomas were associated with dynamic quantitative changes in the subpopulations of macrophages with the morphofunctional characteristics of M1 and M2 phenotypes, determining the antibacterial and destructive potential of granulomas. These data are useful for understanding the contribution of functional polarization of macrophages to the pathogenesis of tuberculous infection and, presumably, its complications.

The Role of Fibroblast Growth Factor Receptor Substrate 2 (FRS2) in the Regulation of Two Activity Levels of the Components of the Extracellular Signal-Regulated Kinase (ERK) Pathway in the Mouse Epididymis1

The components of the extracellular signal-regulated kinase (ERK) pathway are involved in the regulation of epididymal cellular processes. Interestingly, our previous studies showed that there are two different activity levels of the ERK pathway components in the epididymal epithelium: a basal level in most regions and a higher level in the differentiated initial segment (IS). In this study we analyzed the role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of these two levels. Two mouse models were generated. In the first model, Frs2 was deleted from epithelial cells of most epididymal regions except for the IS from the embryonic period onward. Loss of Frs2 dampened the basal activity level of the ERK pathway components, which resulted in an increase in apoptosis along the epididymal duct. This was observed during the period when FRS2 expression level was highest in wild-type epididymides. In the second model, Frs2 was deleted from the proximal epididymal epithelium from Postnatal Day 17 onward. Most of the epididymides in this model exhibited normal morphology. Loss of Frs2 in these epididymides did not affect the high activity level of the ERK pathway components in the IS. However, a subgroup of epididymides in the second model showed increased apoptosis which resulted in an abnormally shaped proximal region or development of granulomas. Therefore, data from these two models showed that FRS2 played different roles in the regulation of two activity levels of the ERK pathway components in the epididymis.

Development of Cholesterol Granuloma in a Temporal Bone Petrous Apex Previously Containing Marrow Exposed to Air Cells

There is ongoing debate on the pathogenic mechanisms of cholesterol granuloma formation in the temporal bone. The purpose of this report is to provide evidence in support of the exposed marrow hypothesis in explaining the pathogenesis of petrous apex cholesterol granuloma. Retrospective single case study. The primary outcome evaluated was the diagnosis of a new cholesterol granuloma in a petrous apex that previously demonstrated radiologic evidence of bone marrow exposed to petrous apex air cells. A patient with a unilateral petrous apex cholesterol granuloma develops a new, contralateral cholesterol granuloma in a hyperpneumatized temporal bone petrous apex shown previously to have medullary bone exposed to air cells. This report implicates the medullary-air cell interface in a hyperaerated temporal bone petrous apex in the development and growth of a petrous apex cholesterol granuloma.

Etiologic link between sarcoidosis and Propionibacterium acnes

Propionibacterium acnes is the only microorganism isolated from sarcoid lesions by bacterial culture. Numerous P. acnes genomes are found in lymph node samples from Japanese and European patients with sarcoidosis, whereas a few genomes are found in some non-sarcoid samples. The high frequency and specificity of detecting P. acnes within sarcoid granulomas suggests that this indigenous bacterium causes granuloma formation in many patients with sarcoidosis. P. acnes is the most common commensal bacterium in the lungs and lymph nodes. Occasional detection of P. acnes in non-granulomatous areas of these organs from non-sarcoid patients suggests that host factors are more critical than agent factors in the etiology of sarcoidosis. A particular protein, i.e., trigger factor, from P. acnes causes a cellular immune response only in sarcoid patients. The P. acnes trigger-factor protein induces pulmonary granulomas in mice sensitized with the protein and adjuvant, but only in those with latent P. acnes infection in their lungs. Eradication of P. acnes by antibiotics prevents the development of granulomas in this experimental model. P. acnes can cause latent infection in the lung and lymph nodes and persists in a cell wall-deficient form. The dormant form is endogenously activated under certain conditions and proliferates at the site of latent infection. In patients with P. acnes hypersensitivity, granulomatous inflammation is triggered by intracellular proliferation of the bacterium. Proliferating bacteria may escape granulomatous isolation, spreading to other organs. Latent P. acnes infection in systemic organs can be reactivated by another triggering event, leading to systemic sarcoidosis.

Extrapulmonary manifestations of sarcoidosis.

Sarcoidosis is a systemic disease characterized by the development of epithelioid granulomas in various organs. Although the lungs are involved in most patients with sarcoidosis, virtually any organ can be affected. Recognition of extrapulmonary sarcoidosis requires awareness of the organs most commonly affected, such as the skin and the eyes, and vigilance for the most dangerous manifestations, such as cardiac and neurologic involvement. In this article, the common extrapulmonary manifestations of sarcoidosis are reviewed and organ-specific therapeutic considerations are discussed.

Sarcoid-like lesion is a frequent benign cause of lymphadenopathy in neoplastic patients: Table 1–

To the Editor: Sarcoidosis is a systemic granulomatous disease of unknown origin, characterised by the widespread development of noncaseating epithelioid cell granulomas in more than one organ system. Clinical and radiographic aspects of sarcoidosis and malignancy might mimic one another, making the distinction between the two difficult in some cases. Cancer and sarcoidosis have been associated in some case series but this association remains controversial; several studies from the literature suggest that this association is not fortuitous [1, 2]. Sarcoidosis may precede, follow or occur concurrently with cancer, both haematological malignancies and solid tumours [2]. We wanted to evaluate the incidence of morphological features of sarcoidosis in patients followed up for previous cancer who develop hilar/mediastinal lymphadenopathies with no pulmonary lesions. We performed a retrospective chart review of all patients who were referred to our pulmonology department (Morgagni Hospital, Forli, Italy) in the period between January 2007 and December 2011 with a new onset of hilar/mediastinal lymphadenopathies (with no pulmonary lesions) during follow-up for previous malignancies. Patients underwent endobronchial ultrasound (EBUS) or transoesophageal ultrasound (EUS) trans-bronchial needle aspiration (TBNA) under deep sedation ( i.v. propofol). Lymphadenopathies were diagnosed 49±69 months after the diagnosis of previous malignancy …

Pyogenic granuloma mimicking peripheral dentinogenic ghost‐cell tumour recurrence: case report and meta‐analytic literature update

AbstractPeripheral (extraosseous) dentinogenic ghost‐cell tumours are extremely rare neoplasms, representing less than 1% of all odontogenic tumours. Only 28 cases (including the present report) are described in literature: the majority of patients (89%) are over 40 years of age (mean: 59.1 ± 20.5 years) and 63% are male. Seventy‐three per cent are located in the mandible, and anterior jaw regions are most commonly affected (74%). Erosion of the underlying bone can be observed in 53% radiographically. The present case report describes a recurrent swelling after excisional biopsy of a peripheral dentinogenic ghost‐cell tumour in the anterior maxilla of a 78‐year‐old male patient mimicking tumour recurrence. Histopathological examination of the second biopsy, however, revealed no evidence of ghost‐cell tumour recurrence but development of a pyogenic granuloma. In contrast to central dentinogenic ghost‐cell tumours, there is no evidence of recurrence of peripheral dentinogenic ghost‐cell tumours in literature to date.

IKKβ in Myeloid Cells Controls the Host Response to Lethal and Sublethal Francisella tularensis LVS Infection

BackgroundThe NF-κB activating kinases, IKKα and IKKβ, are key regulators of inflammation and immunity in response to infection by a variety of pathogens. Both IKKα and IKKβ have been reported to modulate either pro- or anti- inflammatory programs, which may be specific to the infectious organism or the target tissue. Here, we analyzed the requirements for the IKKs in myeloid cells in vivo in response to Francisella tularensis Live Vaccine Strain (Ft. LVS) infection.Methods and Principal FindingsIn contrast to prior reports in which conditional deletion of IKKβ in the myeloid lineage promoted survival and conferred resistance to an in vivo group B streptococcus infection, we show that mice with a comparable conditional deletion (IKKβ cKO) succumb more rapidly to lethal Ft. LVS infection and are unable to control bacterial growth at sublethal doses. Flow cytometry analysis of hepatic non-parenchymal cells from infected mice reveals that IKKβ inhibits M1 classical macrophage activation two days post infection, which has the collateral effect of suppressing IFN-γ+ CD8+ T cells. Despite this early enhanced inflammation, IKKβ cKO mice are unable to control infection; and this coincides with a shift toward M2a polarized macrophages. In comparison, we find that myeloid IKKα is dispensable for survival and bacterial control. However, both IKKα and IKKβ have effects on hepatic granuloma development. IKKα cKO mice develop fewer, but well-contained granulomas that accumulate excess necrotic cells after 9 days of infection; while IKKβ cKO mice develop numerous micro-granulomas that are less well contained.ConclusionsTaken together our findings reveal that unlike IKKα, IKKβ has multiple, contrasting roles in this bacterial infection model by acting in an anti-inflammatory capacity at early times towards sublethal Ft. LVS infection; but in spite of this, macrophage IKKβ is also a critical effector for host survival and efficient pathogen clearance.

Neurosarcoidosis in a patient treated with tumor necrosis factor alpha inhibitors

We describe the case of a 36-year-old Caucasian man with a 9-year history of HLA-B27-positive ankylosing spondylitis, who presented with new seizures. He had a non-focal neurological exam. Blood tests showed mild leukocytosis and elevation in liver transaminases. Initial head CT showed hypodensity in the left frontal subcortical white matter. MRI of the brain showed leptomeningeal enhancement and several hyperintense lesions (Fig. 1a–c). He had been on adalimumab (Humira ) for 3 years, but this was discontinued as a repeat MRI showed progression and increased size of the lesions 1 month later. He was then treated with intravenous SoluMedrol at 1 g/day for 5 days with prednisone taper and maintained on methotrexate. CSF studies showed mild lymphocytic leukocytosis and elevated protein. EEG showed bihemispheric slowing; left worse than right. Brain biopsy showed well-formed non-caseating granulomas consistent with neurosarcoidosis (Fig. 2a–c). Leading up to this presentation, he had also been treated with etanercept (Enbrel ) for 2 years prior to adalimumab. Tumor necrosis factor alpha inhibitors (TNFAIs) include etanercept (Enbrel )—a TNFa p75 soluble receptor fusion protein; and adalimumab (Humira ) and infliximab (Remicade )—both monoclonal antibody to TNFa. Despite the efficacy of TNFAIs in many autoimmune arthropathies and refractory sarcoidosis, treatment with these agents may have a paradoxical effect, as seen in this case. Neurosarcoidosis, in the presence of multisystem organ involvement and neurologic deficits, has an incidence of approximately 1 per 100,000 and is present in 5 % of systemic sarcoidosis cases [1]. It has been found strictly confined to the CNS in approximately 0.2 per 100,000. CNS involvement usually reveals granulomatous infiltration of the meninges and parenchyma, most prominent at the base of the brain [2, 3]. The etiology of sarcoidosis remains unknown; however, it may possibly be linked to genetic susceptibility with increased Th1 immune response to environmental factors [4]. TNFa is one of the main cytokines responsible for initiation and formation of granulomas; therefore, besides cytotoxic drugs such as methotrexate, azathioprine, and cyclosporine, TNFAIs have been used in some refractory cases of sarcoidosis [5, 6]. Combination treatment with mycophenolate mofetil and infliximab was shown to be effective in treating neurosarcoidosis [7]. Considering this known pathological correlation and efficacy of TNFAIs, it is somewhat surprising and paradoxical that TNFAIs would cause granulomatosis. Tong et al. [8] summarized a total of 37 cases of sarcoidlike granuloma development after TNFAIs therapy. This phenomenon was reported in all three TNFAIs, suggesting this is a ‘‘class effect’’ [8–10]. Almost all cases are peripheral sarcoidosis of the lungs and skin [8]. There was only one case of neurosarcoidosis reported in a 41-year-old female being on infliximab and methotrexate for rheumatoid arthritis [11]. In our case, the temporal relationship between neurosarcoidosis development while being on etanercept and adalimumab, and resolution of the disease while being off the agents, is highly suggestive of causality. We did not rechallenge the patient with another TNFAI as there has been previous reports on recurrence of sarcoidlike granulomas with rechallenging [8, 12]. Y. Mao-Draayer (&) Neurology Department, University of Michigan, Ann Arbor, MI 48103, USA e-mail: maodraay@med.umich.edu

New Perspectives on Ancient Granulomas

EDITORIAL article Front. Immunol., 15 November 2013Sec. Inflammation Volume 4 - 2013 | https://doi.org/10.3389/fimmu.2013.00345

The linkage of innate and adaptive immune response during granulomatous development

Granulomas represent a spectrum of inflammatory sequestration responses that may be initiated by a variety of agents, including non-infectious environmental factors and infectious microbial pathogens. Although this reaction is designed to be protective, the associated tissue injury is often responsible for a profound degree of pathology. While many of the mechanisms that sustain the development of the granuloma are enigmatic, it is accepted that the maintenance of this inflammatory process is dependent upon dynamic interactions between an inciting agent, inflammatory mediators, various immune and inflammatory cells, and structural cells of the involved tissue. The best studied of the host-dependent processes during granuloma development is the innate and adaptive immune response. The innate immune response by antigen-presenting cells [APCs; dendritic cells (DCs) and macrophages] is initiated quickly to protect from overwhelming pathogens, but with time, can also activate the adaptive immune response. APCs, essential regulators of the innate immune response, can respond to microbial ligands through Toll-like receptors (TLRs), which function in the recognition of microbial components and play an important role to link the innate and adaptive immune responses. CD4+ T helper (Th) cells are essential regulators of adaptive immune responses and inflammatory diseases. Recently, the Notch system has been shown to be an important bridge between APCs and T cell communication circuits. In the present review, we discuss recent findings that explore the mechanisms in the linkage of innate and adaptive immunity, including granulomatous formation though TLRs and Notch activation.

Utility of acid fast staining and re-aspiration in tubercuhlar lymphadenopathy - 3 year study at tertiary centre

Background: Tuberculosis is a great problem throughout the world, especially in developing countries like India. Beside pulmonary tuberculosis, extra pulmonary tuberculosis is relatively more common among the Asian population. Aims & Objective: (1) To establishing the utility of performing Acid Fast Bacilli (AFB) on aspirated material; (2) To study the distribution of cytomorphological patterns of tuberculous lymphadenitis; (3) To study the role of repeat aspiration in diagnosing tuberculous lymphadenitis. Material and Methods: The present study was conducted on 1022 patients of lymphadenopathy during the period of 36 months. Fine needle aspiration was performed in all the patients and 3 smears are made. One is kept unfixed for Ziehl Neelsen staining and other two are alcohol fixed and stained with Papanicolaou (Pap) stain and May Grunwald Giemsa (MGG) stain. Results: Out of 1022 aspirations from lymph nodes 402 cases were diagnosed as tuberculous (TB) lymphadenitis. Three cytomorphological patterns were observed: group-1: Granulomas without necrosis (33.83%); group-2: Caseating epithelioid granulomas (43.03%); and group-3: Necrotizing lymphadenitis (23.13%). AFB positivity was seen in 44.02% cases. 125 cases were diagnosed as reactive lymphadenitis with activated histiocyte clusters were advised a repeat aspiration, out of these 55 cases showed subsequent development of epithelioid granulomas. Conclusion: FNAC is a useful tool in the study of tuberculous lymphadenitis and repeat aspiration, after 2 – 3 weeks helps in providing the correct diagnosis of early tubercular lesions.

Lack of IRF-1 accelerates development of tubulointerstitial nephritis and pulmonary granulomas with predominant Th2 polarity in lupus-prone MRL/lpr mice

Lack of IRF-1 accelerates development of tubulointerstitial nephritis and pulmonary granulomas with predominant Th2 polarity in lupus-prone MRL/lpr mice

Within the Enemy’s Camp: contribution of the granuloma to the dissemination, persistence and transmission of Mycobacterium tuberculosis

Pulmonary tuberculosis, caused by Mycobacterium tuberculosis (M.tb) represents a leading global health concern, with 8.7 million newly emerging cases, and 1.4 million reported deaths annually. Despite an estimated one third of the world’s population being infected, relatively few infected individuals ever develop active clinical disease. The ability of the host to remain latently infected while preventing disease is thought to be due to the generation of a robust type 1 immune response in the lung, capable of controlling, but not clearing, M.tb. A key feature of the type 1 immune response to M.tb is the formation of immune cellular aggregates termed granuloma. The granuloma structure has long been considered a hallmark of host’s protective response toward M.tb. Historically, a correlative relationship between granuloma formation/maintenance and bacterial control has been seen in models where disrupted granuloma formation or structure was found to be fatal. Despite this established relationship much about the granuloma’s role in M.tb immunity remains unknown. Recent publications suggest that the granuloma actually aids the persistence of M.tb and that the development of a necrotic granuloma is essential to person-to-person transmission. Our group and others have recently demonstrated that enclosed within the granuloma is a population of immunologically altered antigen-presenting cells and T lymphocyte populations. Of note, the ability of these populations to produce type 1 cytokines such as interferon-gamma, and bactericidal products including nitric oxide, are significantly reduced, while remaining competent to produce high levels immunosuppressive interleukin-10. These observations indicate that although the chronic granuloma represents a highly unique environment, it is more similar to that of a tumor than an active site of bacterial control. In this review we will explore what is known about this unique environment and its contribution to the persistence of M.tb.

Etiologic Aspect of Sarcoidosis as an Allergic Endogenous Infection Caused byPropionibacterium acnes

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Propionibacterium acnes is the only microorganism that has been isolated from sarcoid lesions. Many P. acnes have been detected in sarcoid lymph nodes using quantitative PCR and in sarcoid granulomas by in situ hybridization. P. acnes trigger factor protein causes a cellular immune response only in sarcoid patients and induces pulmonary granulomas in mice sensitized with the protein and adjuvant, but only those with latent P. acnes infection in their lungs. Eradication of P. acnes by antibiotics prevents the development of granulomas in this experimental model. Although P. acnes is the most common commensal bacterium in the lungs and lymph nodes, P. acnes-specific antibody detected the bacterium within sarcoid granulomas of these organs. P. acnes can cause latent infection in the lung and lymph node and persist in a cell-wall-deficient form. The dormant form is activated endogenously under certain conditions and proliferates at the site of latent infection. In patients with P. acnes hypersensitivity, granulomatous inflammation is triggered by intracellular proliferation of the bacterium. Proliferating bacteria may escape granulomatous isolation, spreading to other organs. Latent P. acnes infection in systemic organs can be reactivated by another triggering event, leading to systemic sarcoidosis.

High IL-4 production related to granuloma development in high-tolerogenic mice infected with Schistosoma mansoni.

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The association between the interleukin-10 cytokine and CC chemokine ligand 5 polymorphisms and mycetoma granuloma formation

Mycetoma is a progressive and destructive chronic granulomatous subcutaneous inflammatory disease caused by bacteria and fungi. The genetic determinants for susceptibility to and the development of mycetoma are unclear. Polymorphisms in genes encoding for cytokines and chemokines usually influence the efficiency of the immune response to infection and are associated with disease susceptibility and progression. Therefore, we hypothesized that polymorphisms of CC chemokine ligand 5 (CCL5) and interleukin-10 (IL-10) promoter regions might contribute to the initiation, susceptibility, and severity of eumycetoma. This case-control study included 149 mycetoma patients and 206 healthy matched controls. In the study population, three functional single nucleotide polymorphisms (SNPs) in CCL5 and two in IL-10 were genotyped using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Significant differences in allele distribution were demonstrated for CCL5 -28 C/G (P < 0.0001), CCL5 In1.1 T/C (P < 0.0001) and IL-10 -592 A/C. Since in previous studies it was demonstrated that the genotypes obtained for CCL5 and IL-10 were connected with CCL5 and IL-10 production we measured the serum levels of CCL5 and IL-10 in mycetoma patients and healthy controls. Elevated serum levels for both CCL5 and IL-10 were found in mycetoma patients and we describe that genetic differences in CCL5 and IL-10 are associated with the development of the mycetoma granuloma.

Evidence Supporting a Protective Role for Th9 and Th22 Cytokines in Human and Experimental Periapical Lesions

IntroductionThe development of periapical granulomas is dependent on the host response and involves Th1, Th2, Th17, and Treg-related cytokines. The discovery of new Th9 and Th22 subsets, with important immunomodulatory roles mediated by interleukin (IL)-9 and IL-22, respectively, emphasizes the need for reevaluation of current cytokine paradigms in context of periapical lesions. We investigated the expression of IL-9 and IL-22 in active and stable human granulomas and throughout experimental lesion development in mice. MethodsPeriapical granulomas (N = 83) and control specimens (N = 24) were evaluated regarding the expression of IL-9 and IL-22 via real-time polymerase chain reaction. Experimental periapical lesions were induced in mice (pulp exposure and bacterial inoculation) and the lesions evolution correlation with IL-9 and IL-22 expression kinetics was evaluated. ResultsIL-9 and IL-22 mRNA expression was higher in periapical lesions than in control samples; higher levels of IL-9 and IL-22 were observed in inactive than in active lesions. In the experimental lesions model, increasing levels of IL-9 and IL-22 mRNA were detected in the lesions, and inverse correlations were found between IL-9 and IL-22 and the increase of lesion area in the different time point intervals. ConclusionsOur results suggest that Th9 and Th22 pathways may contribute to human and experimental periapical lesion stability.