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Year : 2015  |  Volume : 6  |  Issue : 3  |  Page : 75-78

Psychoneuroimmunology of immune reconstitution inflammatory syndrome: Relevance of oral manifestations

UCLA School of Dentistry, Los Angeles, California, USA

Date of Web Publication28-Aug-2015

Correspondence Address:
Francesco Chiappelli
UCLA School of Dentistry, Los Angeles, California
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2155-8213.163809

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How to cite this article:
Chiappelli F. Psychoneuroimmunology of immune reconstitution inflammatory syndrome: Relevance of oral manifestations. Dent Hypotheses 2015;6:75-8

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Chiappelli F. Psychoneuroimmunology of immune reconstitution inflammatory syndrome: Relevance of oral manifestations. Dent Hypotheses [serial online] 2015 [cited 2023 Jun 2];6:75-8. Available from:

Over one-third of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients under antiretroviral (ARV) treatment develop the immune reconstitution inflammatory syndrome (IRIS). The variables that predispose for IRIS are not fully understood. Among the most striking features of IRIS, are aggressive resurgence HIV/AIDS-related cancers and oral manifestations of HIV/AIDS that include oral Kaposi, hairy leukoplakia, and oral ulcers such as recurrent aphthous stomatitis (RAS). Since the etiology for RAS may include anxiety, the hypothesis is projected that anxiety and related psychoemotional states might be significant predictors of IRIS by altering the psychoneuroimmune regulation. We suggest that temporomandibular joint disorders (TMDs) may also be uncovered in IRIS. A well-articulated translational health care program is timely and critical for the relevance of oral manifestations of IRIS such as RAS and TMD.

Over one-third of the patients seropositive for HIV, with signs of AIDS and under treatment with ARV interventions develop IRIS. [1],[2],[3] It is not clear what variables determine whether a patient with HIV/AIDS will develop ARV-related IRIS but the BEB so far indicates that HIV/AIDS patients with low cluster of differentiation 4 (CD4) cell count and HIV/AIDS patients whose CD4 count recovery show a sharp slope, have a particularly fast "immune reconstitution" and are at greater risk of developing IRIS. [2],[3] Still, even after taking into account these two significant predictors, the medical establishment is currently at a loss to explain the variables that may determine rather important odds for ARV-related IRIS. [1]

IRIS may be a misnomer. Indeed, the concept of "immune reconstitution" is unclear, simplistic, enigmatic, and confusing. Immune surveillance mechanisms are finely regulated, cellular, and physiologic processes that involve more that just CD4 cell number. There is a vast literature that describes the role of neuroendocrine modulation of cellular immunity. In addition, there is ample evidence to support the intertwined biological effects of psychological and physiological factors on health and disease including HIV/AIDS and oral biology and medicine: [4],[5] Therefore, the fields of scientific endeavors now referred to as "psychobiology," "psychoneuroendocrinology," "biological psychiatry," "psychoimmunology," and "psychoneuroimmunology" evolved. Physiology is a delicately intertwined network: Case in point, bone metabolism is intimately linked to cellular immune regulation (i.e., osteoimmunology) and the BEB supports the concept that osteoimmunology and psychoneuroimmunology cannot be extricated; hence, the novel domain of inquiry known as psychoneuroendocrinology-osteoimmunology. [6] We discussed the relevance of this field in HIV/AIDS with immunophysiological process that requires and involves a plethora of cytokines and factors that are not cytokines. Together, these elements are involved in a delicately balanced orchestra of effects and counter-effects, activation, and feedback loops that together signify the fine regulation of cellular immune surveillance. We have recently discussed certain aspects of the vast immune-inflammation microenvironment as it pertains to viral immune surveillance including dengue [8] and Ebola. [9] This discussion should be expanded to HIV/AIDS in general and IRIS in particular. In brief, we might simplistically view an inflammatory response as composed of two phases: The first triggered and sustained by myeloid CD45+CD14+ cells (some of which are CD4+ dim ) that produces interleukin (IL)6, ILb and tumor necrosis factor (TNF)a in addition to prostaglandins and other non-cytokines that favor inflammatory processes - this is a rather sharp and short-lived response; the second triggered by lymphoid CD45+CD14 cells (many of which are CD4+ high ) that engender a T helper (TH)17 response (i.e., predominant cytokines: IL17 and IL23) that is finely regulated by IL9 and other TH9 cytokines representatives - this, by contrast, is a sustained inflammation such as observed in inflammatory diseases (e.g., inflammatory bowel disease). Both arms are subject to fine regulation brought up in part by regulatory T cells (CD4+CD25+FoxP3+). [5],[8],[9] In other words, within the fast-rising CD4 cell count observed in IRIS, it is important to distinguish which subpopulation of CD4+ cell is fast-proliferating.

While we understand the term "inflammatory syndrome" to mean a state of chaotic inflammation where regulatory feedback loops are dysfunctional, it is hard to comprehend how and why the medical establishment selected a term to so obviously counter the BEB we have about cellular immunity, and designated "immune reconstitution" as simplistically as recovered CD4 cell numbers. However, the term IRIS is here to stay in the medical nomenclature and we must study it as the pathological characteristics that it manifests. Among the most striking features of IRIS, are aggressive resurgence of HIV/AIDS-related cancers such as Kaposi sarcoma and Hodgkin and non-Hodgkin lymphomas and a reoccurrence of oral manifestations of HIV/AIDS including oral Kaposi, hairy leukoplakia, and oral ulcers. Among the latter, clinical evidence indicates that RAS have a disturbingly high prevalence. [1],[2],[3],[10],[11],[12]

This observation is somewhat surprising because RAS is traditionally not an oral manifestation in HIV/AIDS, even before the onset of ARV treatment interventions. On the other hand, and returning to our quest of what are the determinant variables that act in concert to favor the onset and progression of IRIS, we may hypothesize on the basis of the extensive psychoneuroimmunology literature previously noted that anxiety and the general psychological or psychiatric state of the HIV/AIDS patient could be a significant predictor of IRIS.

The BEB available to date indicates that anxiety and other psychoemotional states (e.g., perception of stress and phobias) are not uncommon among patients with HIV/AIDS, [13],[14] in part due to the social stigma associated with their status, in part for the awareness of life expectancy and quality of life issues, and in part due to incipient neuro-AIDS, the biomarkers of which are still under active investigation. [15] In support of our hypothesis is also the widespread observation that one component of the idiopathic etiology for RAS is attributable to the patient's perception of stress and state of anxiety; in our own work, we discussed RAS as an allostatic response type I. [16] Thirdly, data suggest that HIV/AIDS patients with incipient IRIS may have the progression of IRIS significantly curbed by having the clinical staff relieve their anxiety by explaining to them that the resurgence of they symptoms they feel and observe is part of the normal and expected side effects of ARV intervention. [10],[11],[12],[13],[14] A corollary to the hypothesis we propose here that anxiety is a significant predictor of IRIS, as monitored by the resurgence of oral Kaposi contemporaneously with the emergence of RAS, leads us to expect increased prevalence of bruxism in IRIS and consequential TMD as well. [7],[17] If this hypothesis is proved to be true, then interventions directed at reducing anxiety, such as mindfulness meditation, [18],[19] delivered either contemporaneously with ARV or immediately at the earliest onset of IRIS symptoms could be expected to prevent full-blown IRIS including associated RAS and TMD.

It is timely and critical to deploy a well-articulated translational health care program to define and characterize the BEB for the relevance of oral manifestations of IRIS such as RAS and TMD. Translational research paradigms for the characterization of biomarkers are as essential as a well-articulated translational effectiveness program for the pursuit and utilization of BEB in specific clinical settings. Systematic reviews of the evidence with qualitative [20] and quantitative consensus (i.e., meta-analysis) of BEB in a comparative effectiveness research (CER) paradigm, including the proposed mindfulness meditation [Figure 1], [21] are of essence. The ultimate goal of this campaign must be, in addition to establishing and confirming the relevance or oral manifestations such as TMD and RAS in the psychoneuroimmunology of IRIS, to disseminate BEB in an effort to increase health literacy among patients and stakeholders and ultimately maximize the benefit and quality of life of patients with HIV/AIDS and HIV/AIDS-related IRIS.
Figure 1: Analytical framework for mindfulness meditation in IRIS. The figure shows the analytical framework for the proposed CER about the intervention (I) (in italics) of mindfulness meditation (MM) and the comparator (C) of controlled breathing and muscle relaxation, administered in a population of patients (P) with HIV/AIDS treated with ARV in pursuit of the clinical outcome (O) of decreased anxiety during a timeline (T) of the length or ARV treatment in the clinical setting (S) proffered by ambulatory dental care within a practice-based research network such as the Evidence-Based Decisions Practice-Based Research Network (EBD-PBRN). Associated with this PICOTS question, are four key questions (KQs 1-4) revealed after consultation with key informants during the process of refinement of PICOTS. All KQs qualify for greater certain specifications of MM intervention (I) (e.g., how often should the directed sessions of MM or the individual sessions of practice be held? KQ1); what might be the adverse effects of engaging in MM on psychoemotional health and well-being? KQ2; might the proposed intervention be actually too short or might it be too long? KQ3; who might be the additional key informants (i.e., stakeholders)? KQ4. Cognizant that additional and more incisive KQs will arise to better inform this CER approach, we propose this figure simply to represent the process

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The author thanks the Evidence-Based Decisions Active Groups of Stakeholders (EBD-AGS) of the EBD Practice-Based Research Network (EBD-PRN) ( (Last accessed on 2015 Jul 27)) and the students and colleagues of the EBD Study Group, in particular Dr. Olivia Cajulis for the edifying discussion about clinical dentistry and ambulatory general dentistry care. This was funded in part by UCLA Senate grants and Fulbright Specialist grant (5077) to the author.

  References Top

Chiappelli F. Psychoneuroimmunology of immune reconstitution inflammatory syndrome (IRIS): The new frontier in translational biomedicine. Transl Biomed 2015;6:1-4.  Back to cited text no. 1
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Espinosa E, Ormsby CE, Vega-Barrientos RS, Ruiz-Cruz M, Moreno-Coutiño G, Peña-Jiménez A, et al. Risk factors for immune reconstitution inflammatory syndrome under combination antiretroviral therapy can be aetiology-specific. Int J STD AIDS 2010;21:573-9.  Back to cited text no. 3
Chiappelli F, Abanomy A, Hodgson D, Mazey KA, Messadi DV, Mito RS, et al. Clinical, experimental and translational psychoneuroimmunology research models in oral biology and medicine. In: Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology. 3 rd ed. Vol. 1. San Diego: Academic Press; 2001. p. 645-70.  Back to cited text no. 4
Chiappelli F, Bakhordarian A, Bach Q, Demerjian GG. Translational psychoneuroimmunology in oral biology and medicine. Forum on immunopathological diseases and therapeutics. 2015. [In Press].  Back to cited text no. 5
Arron JR, Choi Y. Bone versus immune system. Nature 2000;408:535-6.   Back to cited text no. 6
Chiappelli F. Osteoimmunopathology: Evidence-Based Perspectives from Molecular Biology to Systems Biology. New York: Springer; 2011. p. 1-137.  Back to cited text no. 7
Chiappelli F, Santos SM, Caldeira Brant XM, Bakhordarian A, Thames AD, Maida CA, et al. Viral immune evasion in dengue: Toward evidence-based revisions of clinical practice guidelines. Bioinformation 2014;10:726-33.   Back to cited text no. 8
Chiappelli F, Bakhordarian A, Thames AD, Du AM, Jan AL, Nahcivan M, et al. Ebola: Translational science considerations. J Transl Med 2015;13:11.   Back to cited text no. 9
Murthy AR, Marulappa R, Hegde U, Kappadi D, Ambikathanaya UK, Nair P. Treatment guidelines and prognosis of immune reconstitution inflammatory syndrome patients: A review. J Int Oral Health  2015;7:92-5.  Back to cited text no. 10
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Barkhordarian A, Ajaj R, Ramchandani MH, Demerjian G, Cayabyab R, Danaie S, et al. Osteoimmunopathology in HIV/AIDS: A translational evidence-based perspective. Patholog Res Int 2011;2011:359242.  Back to cited text no. 17
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