A case report of lymphoid intestitial pneumonia in common variable immunodeficiency: Oligoclonal expansion of effector lymphocytes with preferential cytomegalovirus-specific immune response and lymphoproliferative disease promotion

Abstract

Rationale: Lymphoid interstitial pneumonia (LIP) is a rare disease with lymphocytic infiltration of the alveolar interstitial and air spaces, sometimes classified as a clonal lymphoproliferative disease (LPD) with high prevalence in patients with immunodysregulation. Although association of mucosa-associated lymphoid tissue (MALT) lymphoma development with infectious agents has been well described, it is not so in the case of LIP. Attempts to demonstrate an infective cause by direct microbe detection have failed, but association with atypical specific immune response to opportunistic infectious agent has not been studied.

Patient concerns and diagnoses: We performed clinical, biochemical, and immunologic analysis of patients LIP that arises primarily from the common variable immune deficiency (CVID) with normal immunoglobulin class M (IgM) level and mild infectious course as a result of immunodysregulation. At the age of 13 multiple nodules, areas of consolidation were observed and LIP was confirmed by histological examination. The progression of the disease with massive splenomegaly (17→27 cm), lymphadenopathy soft tissue infiltration coincides with high standardized uptake value (SUV was 3.1-5.2), regulatory T cells decrease (CD4+25FoxP3+ level -0.02%, i.e., 8 cells per 100 μL), oligoclonal gammapathy: very high IgM (3340 mg/dL) and β2-microglobulin (18.8 mg/L) level observed 10 years later.Immune response polarization was observed in humoral and cellular compartment -Th and Tc-dependent: 10.8% of lymphocytes are CD8high+CMV pp65-pentamer positive cells (Epstein-Barr virus-specific not observed). Specific immune response polarization correlates with negative immunofixation, light chains κ/λ = 2.84 and narrow, but non-monoclonal T cell receptor (TCR)/ B cell receptor (BCR) repertoire.

Lessons: Taking everything into account, this case report shows that LIP is a consequence of immune-dysregulation in CVID, that is, Treg deficiency, narrow lymphocyte repertoire, and abnormal ability to respond to cytomegalovirus (CMV) antigens. It may be visualized by positron emission tomography (PET) and monitored by CMV-specific immune response, β2-microglobulin level, and IgM paraproteinaemia, but not by immunofixation and κ/λ ratio.

Figure 1

Pathogenesis and prognostic factors of lymphoid interstitial pneumonia. Lymphocyte polarization, that is, narow B cell (BCR) and Tcell receptor (TCR) repertoire (A) as a source of non-monoclonal gammapathy (B) and lymphoproliferative disease visualized by Positron emission tomography (PET) (C). (A) BCR -immunoglobulins heavy chains (IgH) and TCR complementary determining regions repertoire analysis. The reduced TCR and BCR diversity in CVID patient (top panel) compared with healthy control patient (bottom). In B cells, IgH were not clonally rearranged, contrary to Waldenstrom macroglobulinemia. The narrow and oligoclonal TCR repertoire resulted in weak immune response to common herpetic viral antigen (e.g., EBV), but vigorous to CMV in γ-interferon release (see Table 1) and CMV-specific CD8 lymphocyte propagation (Table 2). (B) In humoral compartment serum sickness and very high level of nonmonoclonal IgM paraproteinaemia with complement consumption were observed. A very dense band in the γ-globulin region of the serum proteins appears polyclonal because of its size in width and great density.^[13] Although immunofixation was negative and light chains κ/λ ratio was insignificant (2.84), TCR/BCR oligoclonal (see, A)—the clinical manifestation and hyperviscosity resembles malignant lymphoproliferative disease (Waldenstrom macroglobulinemia, lymphoma). (C) Positron emission tomography (PET) during progression of the lymphoproliferative disease. Highest uptake of ⁽¹⁸⁾F-fluoro-deoxyglucose was seen in pulmonary granulomas with lymphoid tissue (standardized uptake value [SUV] was 3.1–5.2). It corresponded with histological findings: high proliferative response (Ki67—50%), lymphoplasmocytoid CD20+CD138+ B cells infiltration and high β2-microglobulin level, known prognostic marker for lymphoproliferative diseasae. CMV = cytomegalovirus; CVID = common variable immunodeficiency, IgM = immunoglobulin class M.

Figure 2

Proposed etiology and pathogenetic factors of lymphoid intestitial pneumonia (LIP) in common variable immunedeficiency (CVID). LIP development in CVID is a result of narrow lymphocyte repertoire, low Treg level and prolonged cytomegalovirus (CMV)-antigenic stimulation. Narrow B (BCR) and T cell receptor (TCR) repertoire, regulatory T cells (Treg) deficiency are a hallmark of immunodysregulation in CVID.^[4,11] High antigenic stimulation by CMV induces bronchus-associated lymphoid tissue (BALT) reappearance, oligoclonal lymphoproliferative disease, and infiltration of intestitial tissue by humoral and cellular hyperactivity (IgM/complement and IFNγ). It may be visualized by positron emission tomography (PET). Red font—immune parameter useful in disease monitoring as a prognostic factor or leading parameter.