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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Am Acad Dermatol. Author manuscript; available in PMC 2017 May 1.
Published in final edited form as:
PMCID: PMC4834432
NIHMSID: NIHMS742046

Immune Dysregulation Underlies a Subset of Patients with Chronic Idiopathic Pruritus

Amy Z. Xu, BS,1,2,3 Shivani V. Tripathi, MD,1,2 Andrew L. Kau, MD, PhD,4 András Schaffer, MD, PhD,1,5,6 and Brian S. Kim, MD, MTR1,2,6,7

To the Editor

Chronic pruritus is a highly debilitating condition that disproportionately affects the elderly, many of whom experience chronic idiopathic pruritus (CIP), or itch of unknown origin lasting greater than six weeks [1, 2]. Multiple factors are believed to underlie CIP, including aging-associated skin barrier dysfunction, sensory neuropathy, and immunosenescence, the waning of immune function that results in an “allergic,” T helper type 2 (Th2) cell response [1, 2]. However, the immunologic profile of CIP patients remains poorly understood.

We report four elderly CIP patients with evidence of marked immune dysregulation after exclusion of other cutaneous and systemic causes of pruritus. Despite the lack of primary dermatologic processes, three out of four patients showed lymphocytic infiltrates on skin biopsy, two of whom demonstrated increased eosinophils (Figure 1, Table I). Immunoglobulin panels and blood flow cytometry revealed previously unrecognized humoral and cellular immune defects, including T and B cell lymphopenia, eosinophilia, and hypogammaglobulinemia (Table I).

Fig 1
Chronic idiopathic pruritus
Table I
Summary of Clinical and Immunologic Characteristics.

Given our patients’ broad immunologic defects, we initially considered whether they had underlying primary immunodeficiencies like common variable immunodeficiency (CVID). However, our patients’ reduced IgG values were not associated with decreases in IgA or IgM, as in CVID. Our patients also lacked any history of CVID-associated complications, such as recurrent infections, autoimmunity, and malignancy. These findings suggest that CIP patients may acquire secondary immune defects resembling CVID as a consequence of the aging process.

Immunosenescence results in a loss of T helper type 1 (Th1) cell-driven protective immunity that contributes to skewing towards an allergic, Th2 response [2, 3]. Indeed, our elderly CIP patients exhibited Th2 polarization as evidenced by their elevated serum IgE levels, peripheral eosinophilia, and/or tissue eosinophil infiltration (Table I). Additionally, their CD8lymphopenia confirms the loss of Th1 responses, further supporting age-dependent Th2 polarization as a potential contributor to the development of chronic itch. Strikingly, comparison to age-matched control populations indicates that our CIP patients suffer from immunologic imbalances in excess of similarly-aged peers [4, 5]. Three of our patients’ CD8+ T cell counts were significantly reduced in comparison to control subjects of corresponding age; for example, the CD8+ T cell count of 67/mm3 in Case 3 was nearly two standard deviations below the mean reported by Provinciali et al. [4]. Likewise, IgG levels for two of our patients (Cases 1 and 3) fell below the bottom 2.5% described for age-matched controls [5]. These findings suggest that CIP patients may have a greater degree of immune dysfunction that results in an increased susceptibility to chronic pruritus, even above the increased risk already recognized in the elderly.

In conclusion, we present a population of CIP patients who exhibit immunologic deficits in association with Th2 polarization. We hypothesize that aging-associated immunosenescence promotes immune dysregulation that may, in part, explain the increased prevalence of chronic pruritus in the elderly. Thus, the restoration of immune homeostasis by recombinant cytokine or immunoglobulin repletion may represent novel therapeutic approaches for chronic itch. Further investigation will be critical in inspiring new avenues of treatment for this debilitating condition.

Acknowledgments

Support for this work was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant K08-AR065577-01 to B.S.K.), National Institute of Allergy and Infectious Disease Asthma and Allergic Diseases Research Center (Grant 1K08AI113184-01A1 to A.L.K), Washington University School of Medicine Digestive Diseases Research Core Center (NIDDK Grant P30 DK52574), Washington University School of Medicine Pulmonary Morphology Core (NIAID Grant U19AI070489), and American Skin Association (Research Grant). A.Z.X. was supported by the Howard Hughes Medical Institute (HHMI) Medical Fellows Program as an HHMI Medical Research Fellow.

We thank members of the Kim laboratory for discussions and critical readings of the manuscript, Mary Tabacchi for research coordination, and our colleagues at the Washington University Dermatopathology Center for their assistance in preparing histopathologic specimens.

ABBREVIATIONS

CIP
chronic idiopathic pruritus
AD
atopic dermatitis
Th1
T helper type 1
Th2
T helper type 2

Footnotes

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Compliance with Ethical Standards:

  • -
    The authors have no conflicts of interest to declare.
  • -
    All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. This study was approved by the Washington University in Saint Louis IRB (Protocol # 201412117).
  • -
    Informed consent was obtained from all individual participants included in the study.
  • -
    The results described have not been reported previously nor are being considered for publication elsewhere.

References

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3. Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Pedersen AN, Skinhøj P, et al. Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans? Clin Exp Immunol. 2002;127:107–14. [PubMed]
4. Provinciali M, Moresi R, Donnini A, Lisa RM. Reference values for CD4+ and CD8+ T lymphocytes with naïve or memory phenotype and their association with mortality in the elderly. Gerontology. 2009;55:314–21. [PubMed]
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