Immunology Dysregulation in Lymphadenitis Tuberculosis : An Observational Study Using Patient' Block Paraffins 2019 Until 2021

Study Overview
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Brief Summary
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Mycobacterium tuberculosis (M. tuberculosis) infection is still a problem that cannot be overcome in Indonesia. In 2018 the number of tuberculosis (TB) sufferers in Indonesia reached more than 850/100,000 population, an increase around 20% from the previous year's incidence. One of the highest number of cases is in East Java Province, which is 38% of the total number of new TB cases in Indonesia. Extrapulmonary tuberculosis (EPTB) according to WHO classification criteria is an M. tuberculosis infection that occurs in tissues and organs outside the lung parenchyma. The incidence rate in Indonesia reaches 1-5% of the incidence of TB thus EPTB may often be forgotten. However, the diagnosis, therapy and monitoring post treatment in EPTB remains difficult to do. The focus of this research is tuberculous lymphadenitis (TB), due to 50% of EPTB cases in Indonesia was lymphadenitis TB. The risk factors for EPTB are immunocompromised conditions, such as HIV infection or comorbid conditions such as chronic kidney disease (CKD) and diabetes mellitus, but the mechanism of EPTB homing is still unclear. The mechanism of EPTB homing, especially TB lymphadenitis, really needs to be known for the development of diagnostics and therapy as well as preventing the occurrence of TB lymphadenitis. The importance of this research is to obtain compounds from the human immune response that can be developed as diagnostic markers and therapeutic targets for tuberculosis infection, especially TB lymphadenitis. Activated macrophages containing M. tuberculosis are carried by lymph flow to lymph nodes, where there is deposition of antigen-antibody complexes which then activate CC Chemokine Receptor-2 (CCR2) on lymphocytes, which are the primary receptors for Chemokine (CC motif) ligands ( CCL)-8 and CCL5, proteins expressed on macrophages containing M. tuberculosis. Activation of CCR2 increases the production of IL-10(10). IL-10 has been responsible for decreasing the secretion of TNF-, IFN-γ, and IL-1β (11). IFN-γ affects the process of M. tuberculosis elimination and the success of TB therapy, so that IL-10 is responsible for the failure of macrophages to eliminate M. tuberculosis. IL-10 also binds to Signal Transducer and Activator of Transcription 3 (STAT3) and STAT3 increases the release of Suppressor of Cytokine Signaling 3 (SOCS3). SOCS3 interferes with IFN-γ signaling for CCR2 recognition of M. tuberculosis-containing macrophages. On the other hand, the mechanism of T lymphocytes and macrophages that activate pro-inflammatory mediators (TNF-, IFN-γ, and IL-1β) and the association of IL-10 activation on STAT3, SOCS3 and CCR2 expression in the incidence of EPTB, especially TB lymphadenitis without TB infection remains unknown.

Detailed Description
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Mycobacterium tuberculosis (M. tuberculosis) infection is still a problem that cannot be overcome in Indonesia. In 2018 the number of tuberculosis (TB) sufferers in Indonesia reached more than 850/100,000 population, an increase around 20% from the previous year's incidence. One of the highest number of cases is in East Java Province, which is 38% of the total number of new TB cases in Indonesia. Extrapulmonary tuberculosis (EPTB) according to WHO classification criteria is an M. tuberculosis infection that occurs in tissues and organs outside the lung parenchyma. The incidence rate in Indonesia reaches 1-5% of the incidence of TB thus EPTB may often be forgotten. However, the diagnosis, therapy and monitoring post treatment in EPTB remains difficult to do. The focus of this research is tuberculous lymphadenitis (TB), due to 50% of EPTB cases in Indonesia was lymphadenitis TB. The risk factors for EPTB are immunocompromised conditions, such as HIV infection or comorbid conditions such as chronic kidney disease (CKD) and diabetes mellitus, but the mechanism of EPTB homing is still unclear. The mechanism of EPTB homing, especially TB lymphadenitis, really needs to be known for the development of diagnostics and therapy as well as preventing the occurrence of TB lymphadenitis. The importance of this research is to obtain compounds from the human immune response that can be developed as diagnostic markers and therapeutic targets for tuberculosis infection, especially TB lymphadenitis. Activated macrophages containing M. tuberculosis are carried by lymph flow to lymph nodes, where there is deposition of antigen-antibody complexes which then activate CC Chemokine Receptor-2 (CCR2) on lymphocytes, which are the primary receptors for Chemokine (CC motif) ligands ( CCL)-8 and CCL5, proteins expressed on macrophages containing M. tuberculosis. Activation of CCR2 increases the production of IL-10(10). IL-10 has been responsible for decreasing the secretion of TNF-, IFN-γ, and IL-1β (11). IFN-γ affects the process of M. tuberculosis elimination and the success of TB therapy, so that IL-10 is responsible for the failure of macrophages to eliminate M. tuberculosis. IL-10 also binds to Signal Transducer and Activator of Transcription 3 (STAT3) and STAT3 increases the release of Suppressor of Cytokine Signaling 3 (SOCS3). SOCS3 interferes with IFN-γ signaling for CCR2 recognition of M. tuberculosis-containing macrophages. On the other hand, the mechanism of T lymphocytes and macrophages that activate pro-inflammatory mediators (TNF-, IFN-γ, and IL-1β) and the association of IL-10 activation on STAT3, SOCS3 and CCR2 expression in the incidence of EPTB, especially TB lymphadenitis without TB infection remains unknown. In this study, Lymphadenitis TB paraffin blocks from patients were collected and screened for immunological responses that TB patients have potential as targets for diagnosis and therapy. The paraffin block samples came from the Anatomical Pathology Laboratory of St. Catholic Hospital. Vincentius A Paulo (RKZ) Surabaya. Existing samples were taken and performed immuno-histochemical (IHC) to define theimmune dysregulation in TB lymphadenitis.

Official Title
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Immunology Dysregulation in Lymphadenitis Tuberculosis : An Observational Study Using Patient' Block Paraffins 2019 Until 2021

Conditions
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Lymphadenitis, Tuberculous, Immune Defect

Intervention / Treatment
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* Other: Immuno-histochemical staining


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Lymphadenitis TB blocked paraffin that already confirmed by the Pathologist and MPT64 staining Exclusion Criteria: broken blocked paraffin due to the storage process
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Lymphadenitis TB<br>The group study was blocked paraffin from lymphadenitis tuberculosis patient that already confirmed diagnosis histopathological anatomy (PA histopathology) | Other: Immuno-histochemical staining<br>* blocked paraffin that suit with inclusion and exclusion criteria proceed with immuno-histochemical staining to define immune dysregulation in lymphadenitis TB<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IHC slides | Histopathology slides stained by immuno-histochemical substrates | 15 November 2021 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphadenitis tuberculosis, C-C Chemokines receptor - 2 (CCR-2), C-C Chemokines ligand - 5 (CCL-5), Cytokines inflammatory