Mechanisms regulating lymphocytic infiltration of the thyroid in murine models of thyroiditis

The autoimmune diseases of the thyroid are the most prevalent autoimmune diseases in man. In these diseases, the thyroid is invariably infiltrated by lymphocytes, which play a major role in pathogenesis. In this review, we discuss the mechanisms associated with lymphocytic infiltration of the thyroid, examining different models of thyroid autoimmune disease in mice.     

The TRH stimulation test in endemic goitre in Greece

Summary The serum T₄=T₄(D), T₃ in vitro uptake=RT₃U and TSH were measured before and 30 min after the injection of 200 µg of TRH in 30 subjects from an iodine deficient area of Central Greece. These persons were divided in two groups of 16 goitrous and 14 nongoitrous patients and the results from each group compared to each other and also with the same parameters obtained from 14 controls subjects, all nongoitrous and from a nonendemic area. It has been found that in this area with a mild iodine deficiency serum T₄ is the only hormone decreased whereas RT₃U and TSH both before and 30 min after TRH injection are normal. There existed however a negative correlation between serum T₄ and TSH in the goitrous group. Why the nongoitrous iodine deficient persons achieve the same compensation without thyroid gland enlargement remains unresolved but it may be stated from the present results that goitre development should be regarded as a maladaptation rather than a compensatory process.This work was supported by the Hellenic Ministry of Social Services.     

Hashimoto''s thyroiditis manifesting monoclonal lymphocytic infiltration.

Hashimoto's thyroiditis (HT) and lymphoma are sometimes difficult to distinguish between. Moreover, lymphoma sometimes develops in a thyroid gland from pre-existing HT. Open- or large-needle biopsy usually distinguishes between them; the specimen may be examined histologically and subjected to immunohistochemistry. Another possible method of examination is fine-needle aspiration biopsy (FNAB). The cells obtained may be evaluated cytologically, and subjected to flow cytometry, using various antibodies. In this study, anti-kappa and anti-lambda antibodies are especially important, as a gross predominance of kappa or lambda B lymphocytes infiltrating the thyroid is evidence for a B cell monoclone. In this study, 15 patients were selected because of their rapidly growing goitres. They all underwent FNAB. Five had cytology typical of HT, and no evidence of monoclonality on flow cytometry. They were diagnosed as HT without further histopathology. The remaining 10 patients had cytology suspected of lymphoma, or evidence of monoclonality on flow cytometry, or both. These patients underwent open- or large-needle biopsy. Only three of them were diagnosed histopathologically as lymphoma; the other seven were diagnosed histopathologically as HT, making 12 cases of HT in all. Five of these 12 cases, and one of the three cases of lymphoma showed flow cytometrical evidence of monoclonality; thus evidence of monoclonality from FNAB, while interesting, does not necessarily serve to differentiate between HT and lymphoma. Furthermore, the immunohistochemical assessment of monoclonality did not correlate with the flow cytometrical assessment. Follow-up evidence will be required to discover whether those patients with a B cell monoclone in their HT are the ones who develop a lymphoma.     

LATS and thyroid autoantibodies

A group of fifty-nine sera from fifty-three patients were bioassayed for LATS and assayed for autoantibodies to human thyroid. Seventy-five per cent had cytoplasmic autoantibodies and 44% contained LATS but the concurrence of these findings did not exceed chance. In a detailed analysis of forty-five of these sera, neither the titre of thyroglobulin antibody nor of cytoplasmic antibody correlated significantly with the LATS response index.     

Serum paraproteins in chronic lymphocytic leukaemia.

The presence of paraproteins in the sera of 10 patients with chronic lymphocytic leukaemia (CLL) was investigated using immunoisoelectric focusing. Monoclonal immunoglobulins were found in nine of these 10 sera. Five sera contained a single monoclonal IgM paraprotein, one serum contained a single monoclonal IgG paraprotein, while three sera contained more than one monoclonal paraprotein--namely, IgM + IgD, IgM + IgG, and IgM + IgD + IgG. The results indicate that the malignant B cells of CLL may be at a later stage of differentiation than previously assumed and serum monoclonal immunoglobulin could be of value as a tumour marker.     

Beta2 microglobulin and lymphocytic infiltration in Sj?gren's syndrome.

We measured salivary beta2 microglobulin concentrations in 49 patients evaluated for Sj?gren's syndrome with a labial salivary-gland biopsy. The salivary concentration was elevated and a significant correlation (P less than 0.001) was found between the concentration and the degree of inflammation seen in the biopsy. Serum concentrations were increased in 135 patients with Sj?gren's syndrome. Striking elevations were seen in patients with associated renal or lymphoproliferative complications. Three patients have an increase in serum beta2 microglobulin concentration in association with exacerbation of their disease, and six a decrease after clinically efficacious therapy. These data indicate that determination of beta2 microglobulin in saiva may provide a simple, noninvasive technic for estimation of the degree of local inflammation in autoimmune disease.     

Renal failure caused by leukaemic infiltration in chronic lymphocytic leukaemia.

A case of B-CLL which was complicated by chronic renal failure due to leukaemic infiltration of the kidney is reported. Treatment with chlorambucil, prednisolone, and renal bed irradiation resulted in a substantial improvement in renal function which persisted until the the patient''s death from marrow failure some eight years later. The temporal association between treatments and response suggested that renal bed radiotherapy had contributed to the improvement in renal function. This case is one of only two reported cases in which chronic renal failure due to CLL has been treated with radiotherapy. It is unique in that the renal response was shown histologically. Leukaemic infiltration of the kidney is common in CLL but, characteristically, is not associated with renal impairment. An improvement in renal function has been described in two patients with acute renal failure after chemotherapy.     

An investigation of endemic goitre during the centuries in sacral figurative arts

Physical appearances of goitrous people as they appear in figurative sacral arts of Italy are documented and discussed. The investigation is a contribution to historical pathology.     

IgG-class insulin autoantibodies in autoimmune thyroid disease

We studied the incidence of insulin autoantibodies (IAA) in 97 patients with autoimmune thyroid disease with an enzyme-linked immunosorbent assay. The sera were also tested for islet cell antibodies (ICA) and thyrotropin receptor antibodies (TRAb). IAA as assessed by a standard deviation score were present in 7 patients (7.2%). None of the patients were seropositive for ICA. Data from this random sampling and a retrospective study of 12 patients on antithyroid drug treatment indicated that the presence of IAA was not associated with TRAb.     

Effect of lymphocytic infiltration on the blood-retinal barrier in experimental autoimmune uveoretinitis.

Using an experimental model of autoimmune uveoretinitis, we have examined the relationship of T cell infiltration in the retina to blood-retinal barrier (BRB) breakdown. Sensitive quantitative in vivo techniques were used to examine BRB permeability to sucrose, a low mol. wt non-transported solute. Electron microscopy was also used to localize extravasated horseradish peroxidase, a macromolecular visual tracer, from the retinal vasculature and to identify the route by which any leakage was occurring. No increase in BRB permeability was found prior to lymphocytic infiltration. By day 10 of the disease inflammatory cells could be seen within the structurally intact retina, which was shortly followed by an increase in the permeability of the BRB to sucrose. Only later in the disease process, when damage to the photoreceptor layer became apparent, did extravasation of the macromolecule HRP occur. At no stage of the disease process was there any detectable damage to inter-endothelial tight junctions. The size-dependancy of tracer extravasation in the initial stages of the disease is indicative of a paracellular route being responsible for the increase in BRB permeability. In later stages of the disease some evidence of horseradish peroxidase filled 'vesicle-like' profiles was observed. We suggest that the devastating complication of BRB breakdown in ocular inflammation is a direct consequence of lymphocytic infiltration.     

Serum non-organ specific autoantibodies in human immunodeficiency virus 1 infection.

Serum samples from 66 seropositive subjects (56 with a history of intravenous drug abuse), including asymptomatic carriers and patients with persistent generalised lymphadenopathy (PGL), AIDS related complex (ARC), and AIDS, were tested by indirect immunofluorescence on rat tissue sections and HEp-2 cells for the presence of antibodies to nuclei, smooth muscle, intermediate filaments (anti-IMF) and microfilaments (anti-MF). Counterimmunoelectrophoresis was also used to detect antibodies to extractable nuclear antigens. Smooth muscle antibodies with the V pattern or antinuclear antibodies, mainly of the speckled type, or anti-IMF, occurred in 35 cases, being widely distributed in all groups. Such an autoantibody response resembles the "viral" autoimmunity described in various infectious diseases and in particular that of non-A, non-B post-transfusion hepatitis. Autoantibodies may be of some prognostic relevance, as the prevalence of smooth muscle antibodies V increased as the disease progressed (asymptomatic carriers 20%, those with PGL 29%, those with ARC 47%, and those with AIDS 63%. In the PGL group autoantibody positivity correlated with the presence of skin anergy. The fact that autoantibodies were more frequently detected in patients with circulating immune complexes suggests that these can contain autoantibodies and the corresponding autoantigens.     

The incidence of lymphocytic thyroid infiltration and Hashimoto's thyroiditis increased in patients operated for benign goiter over a 31-year period

The incidence of Hashimoto's thyroiditis (HT) seems to have increased over the last several decades. Since there is a lack of recent studies in the literature that evaluate this phenomenon on a histological basis, we aimed to assess the incidence of lymphocytic thyroid infiltration (LTI) in our large surgical patient collective over a 31-year period. In our study, a total of 1,050 patients who had undergone uni- or bilateral thyroid surgery for benign goiter were included (150 patients in each group, during 1979 to 2009). The stored histological sections of the removed thyroid specimens were re-analyzed, including routine grading of LTI severity on a scale of 0–4, according to Williams and Doniach. Positive correlations were seen for the incidences of LTI grading (0–4) (r = 0.077, p = 0.013) and HT (r = 0.044, p = 0.078) over the years. Furthermore, when comparing the years 1979–1989 and 1994–2009, i.e., before and after the second iodine prophylaxis had been introduced in Austria, a higher incidence of HT was found for the later years (2 out of 450, 0.4%, vs. 6 out of 600, 1.0%, respectively; p < 0.0001). In conclusion, the data demonstrate that the incidence of LTI and HT has increased substantially over the last 31 years.     

Ultrastructural aspects of the thyroid in a case of human congenital goitre with cretinism.

Transmission electron microscope and scanning electron microscope studies in a case of congenital goitre associated with cretinism revealed the existence of two cell types: the first with rounded endoplasmic cisternae and normal lysosomes; the second characterized by an abundance of lysosomes and/or lipofuscin granules. Intermediary aspects suggested that the second cell type was the progeny of the first type. As colloid droplets and apical pseudopods engulfing colloid were nearly absent, and as NBE127I was elevated in the plasma, it is suggested that iodoprotein secretion occurred by a process different from colloid phagocytosis as observed after acute TSH stimulation.