Rubella Virus-Associated Cutaneous Granulomas in an Adult With TAP1 Deficiency Case Report

doi:10.21203/rs.3.rs-3448003/v1

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Rubella Virus-Associated Cutaneous Granulomas in an Adult With TAP1 Deficiency Case Report

https://doi.org/10.21203/rs.3.rs-3448003/v1

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Rubella virus-associated granulomas commonly occur in immunocompromised individuals, exhibiting a diverse range of clinical presentations. These manifestations can vary from predominantly superficial cutaneous plaques or nonulcerative nodules to more severe deep ulcerative lesions, often accompanied by extensive necrosis and significant tissue destruction. TAP1 deficiency, an exceedingly rare primary immunodeficiency disorder, presents with severe chronic sino-pulmonary infection and cutaneous granulomas. This report constitutes the inaugural documentation of rubella virus-associated cutaneous granulomas in a patient with TAP1 deficiency. This novel observation holds potential significance for the field of diagnosis and investigative efforts in the context of immunodeficiency disorders.

Rubella Virus

Cutaneous granuloma

TAP1 deficiency

Immunodeficiency

We present the case of A 34-year-old female with rubella virus-associated cutaneous granulomas and TAP1 deficiency, which constitutes the inaugural documentation and holds potential significance for the field of diagnosis and investigative efforts in the context of immunodeficiency disorders.

This is a case report and a detailed description of the clinical course of diagnosis and treatment of rubella virus-associated cutaneous granulomas with TAP1 deficiency. Local ethics vote is not needed because patient signed informed consent and no study was performed.

A 34-year-old female patient presented with a seven-year history of non-painful plaques affecting her right leg, which had recurrently progressed to ulceration and crusting. Upon physical examination, the clinical presentation revealed infiltrated dark red plaques distributed across the right lower extremity, overlaying discrete circular superficial ulcers characterized by a lack of exudation (Fig. 1). Notably, no palpable enlargement of nearby superficial lymph nodes was detected. The patient's medical history and prior diagnostic and therapeutic interventions had already excluded bacterial, fungal, and tubercular etiologies. Despite these investigations, the patient's condition had continued to deteriorate, prompting consideration of autoimmune diseases as a potential underlying cause, including the possibility of vasculitis. Laboratory analysis of peripheral blood revealed the presence of a specific cellular immune deficiency in the patient, characterized by a decreased count of CD3 + T cells (499.48 cells/µl) and NK cells (69.52 cells/µl) (Table 1). To further refine the diagnosis, a skin biopsy was performed, and a portion of the tissue was subjected to metagenomic next-generation sequencing (mNGS) testing. Histopathological examination revealed dense granulomatous inflammation with variable lymphocytic infiltration. The overall granulomatous patterns exhibited a palisaded, sarcoidal, and suppurative nature with caseation (Fig. 2A-B). Immunohistochemistry results indicated that the predominant infiltrating cells within the granuloma were CD4+/CD8 + positive lymphocytes and CD68+/CD163 + macrophages (Fig. 2C). Various staining techniques, including Gram, periodic acid–Schiff, and acid-fast bacteria stains, as well as tissue cultures for bacteria, fungi, and mycobacteria, yielded negative results. Notably, the tissue mNGS test suggested the presence of Rubella Virus (RuV) (sequence number 368, confidence level 99%).

Table 1

Laboratory tests of the patient
Tests	Results	Reference ranges
Total white blood count (WBC)	4.39 × 10⁹/L	4.00–10.00 × 10⁹/L
Neutrophils count (Neut)	2.94 × 10⁹/L	1.80–6.40 × 10⁹/L
Lymphocyte count (LY)	0.97 × 10⁹/L	1.00-3.30 × 10⁹/L
CD3⁺CD19⁻T Cell	499.48/ul	603.00-2993.00/ul
CD3⁻CD19⁺B Cell	530.55/ul	107.00-698.00/ul
CD3⁺CD4⁺T Cell	351.11/ul	441.00-2156.00/ul
CD3⁺CD8⁺T Cell	122.35/ul	125.00-1312.00/ul
CD3⁻CD16⁺CD56⁺NK Cell	69.52/ul	95.00-640.00/ul
IFN gamma Antibodies(Blood)	negative	negative
metagenomic next-generation sequencing (mNGS) (biopsy tissue sample)	Rubella virus	negative
RuV RNA test(Skin biopsy tissue)	negative	negative
RuV RNA test (Blood)	negative	negative
Serum RuV IgG titers	0.05	≤ 1.2
Serum RuV IgM titers	༞500.00 IU/mL	0.00–5.00 IU/mL

Consequently, we initiated additional RuV-related assessments. Upon further inquiry, the patient denied prior MMR (measles, mumps, and rubella) vaccination and any history of prior RuV infection. Strikingly, her RuV IgG titer was significantly elevated (> 500 IU/mL), while RuV IgM remained seronegative. Regrettably, tissue PCR testing for RuV RNA returned negative results. Considering the patient's medical history and the corroborative laboratory findings, the diagnosis of RuV-associated granuloma was established.

Given the possibility of an underlying immunodeficiency, Whole Exome Sequencing was undertaken, revealing a homozygous mutation in the TAP1 gene. Treatment modalities employed included surgical resection, intralesional injection of interferon α-2b, and topical application of imiquimod. The treatment plan and follow-up are currently ongoing, with initial indications suggesting that surgical resection may be the more efficacious therapeutic approach.

Rubella virus (RuV) is a single-stranded RNA virus capable of inducing persistent infections that can lead to various associated pathologies ^[1]. Notably, in 2014, RuV was detected in disseminated cutaneous granulomas afflicting three patients diagnosed with primary immunodeficiency diseases (PID), marking the first documented instances of such an occurrence^[2]. Interestingly, the RuV sequences found in these patients exhibited variation from currently circulating strains but shared striking similarity with the Wistar 27/3 vaccine strain. Subsequent evidence for RuV genomic RNA within the nasopharyngeal cavities of patients diagnosed with PIDs strongly indicated the ongoing replication and evolution of the rubella vaccine in those individuals ^[2–8].

RuV positive granulomas have been reported to develop 2-152 weeks (average 48 weeks) after MMR vaccination typically affecting the skin of the limbs (especially around the site of vaccine administration) ^[3.8]. The severity of RuV-associated granulomatous inflammation exhibits a wide spectrum, ranging from a limited number of superficial cutaneous plaques or nonulcerated nodules to more severe presentations featuring deep ulcerated lesions accompanied by necrosis ^[9]. In patients presenting with RuV-associated granulomas, serological testing revealed a distinctive profile. Specifically, serum samples from these patients tested negative for RuV-IgM. Conversely, RuV-IgG titers were significantly elevated, with values falling within a range of 580–1623 IU/mL. These elevated IgG titers far exceeded those typically observed in immunologically intact individuals following Rubella vaccination, which typically average around 40 IU/mL^[6.10]. In our case, this patient displayed characteristic lower extremity cutaneous manifestations and marked elevation in RuV IgG levels, aligning with patterns observed in previous reports.

RuV-associated granulomas are predominantly sarcoidal epithelioid type consisting of M2 type (CD68+/CD206 + and CD68+/CD163+) macrophages harboring RuV antigen at the granuloma center surrounded by lymphocytes. Based on the identity of cells harboring RuV capsid protein (RVC) antigen and their distribution in the lesions, four distinct granuloma patterns can be classified: M-type RuV-associated granuloma, M(n)-type RuV-associated granuloma, N-type RuV-associated granuloma and DNI-type RuV-associated granuloma ^[3]. It is interesting that the characteristic feature of all granuloma patterns was a substantial presence of T cells even though most individuals had low T-cell counts or defective T-cell cytotoxicity ^[3]. The histopathological examination of our case reveals a distinctive amalgamation of necrotizing and non-necrotizing granulomas within a single biopsy specimen. Notably, this histological pattern is marked by the presence of CD68+/CD168 + M2 macrophages, encircling acellular necrotic centers. These necrotic centers exhibit dense infiltration by CD3 + T cells and, in some instances, the presence of neutrophils is noted, positioned in the interstitial space between the ring of macrophages and the necrotic centers. This histological configuration closely aligns with the characteristic features associated with M(n)-type Rubella virus (RuV)-associated granulomas.

Major Histocompatibility Complex (MHC) class I deficiency syndrome, also recognized as Bare Lymphocyte Syndrome (BLS) type II, is attributed to deficiencies in TAP1, TAP2, or Tapasin ^[11]. Among individuals with TAP1 deficiency, a significant proportion manifests severe, chronic bacterial infections affecting the respiratory tract and/or experiences the development of severe, chronic cutaneous granulomatous lesions mimicking Wegener’s granulomatosis during adolescence or early adulthood ^[12]. Interestingly, viral infections are not prominent in TAP1 deficient patients. It is presumed that TAP-independent immune responses provide adequate protection against viral infection^[13], or alternatively, immune tolerance may develop over time in response to these pathogens. Nonetheless, the patient we have presented in this report was diagnosed with TAP1 deficiency and concurrently experienced the complicating factor of RuV-induced cutaneous granuloma, thus highlighting a unique clinical scenario. Sukriti et al.^[14] reported that diminished expression of TAP1 can result in impaired viral antigen presentation, thereby compromising the effective clearance of hepatitis B virus (HBV). This observation may offer insights into the mechanisms underlying chronic RuV infections in individuals with TAP1 deficiency. Nevertheless, this presumption warrants further validation through additional cases and comprehensive research.

This case provides valuable diagnostic insights. In general, when patients with chronic cutaneous granulomatous lesions fail to respond to immunosuppressive or antibiotic therapies, there should be a consideration for specific pathogenic infections. Molecular diagnostic techniques such as PCR or mNGS applied to skin biopsy tissues can aid in confirming the presence of these infections. It is worth noting that using secretions for PCR or mNGS is not recommended due to their lower diagnostic yield compared to tissue samples. Upon the diagnosis of RuV-associated granulomas, it is imperative to consider the possibility of underlying immune deficiencies. Live rubella vaccines are contraindicated for individuals who have, or are potentially at risk of developing, severe antibody deficiencies, T-cell deficiencies, or innate immune defects^[15].

In this current report, we present the first documented case of a TAP1-deficient patient afflicted by a chronic RuV infection. We offer insights and recommendations pertaining to the diagnostic approach for such cases. The intriguing question of whether granulomas observed in patients with TAP1 deficiency serve as a compelling long-term reservoir for persistent RuV infection or if RuV infections contribute to the initiation and development of granulomas warrants further in-depth investigation.

Statements and Declarations

Competing interests The authors declare no competing interests.

Acknowledgements The authors thank Dr. Li Yang, of The First Affiliated Hospital of Sun Yat-sen University, for her assistance in pathology.

Authorship Contributions All authors contributed to the study conception and design. Qiaohui Wang and Huilin Su had full access to all the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis and contributed equally to this study. Naiyu Lin make critical revision of the manuscript for important intellectual content. Jiande Han and Naiyu Lin provide administrative, technical, or material support. All authors read and approved the final manuscript.

Data Availability All data pertaining to the report are included within the manuscript.

Materials Availability All data pertaining to the report are included within the manuscript.

Ethics approval For this case report no approval was needed by the Ethics Committee because no study was performed.

Consent to participate Written informed consent was obtained from the patient.

Consent for publication The authors affirm that the patient provided informed consent for publication of the data and images in table and figures.

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Rubella Virus-Associated Cutaneous Granulomas in an Adult With TAP1 Deficiency Case Report

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