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. 2000 Aug;47(2):215–227. doi: 10.1136/gut.47.2.215

Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-γδ expression

M Yeung 1, S Melgar 1, V Baranov 1, A Oberg 1, A Danielsson 1, S Hammarstrom 1, M Hammarstrom 1
PMCID: PMC1728017  PMID: 10896913

Abstract

BACKGROUND AND AIMS—A histopathological feature considered indicative of ulcerative colitis (UC) is the so-called basal lymphoid aggregates. Their relevance in the pathogenesis of UC is, however, unknown. We have performed a comprehensive analysis of the immune cells in these aggregates most likely corresponding to the lymphoid follicular hyperplasia also described in other colitides.
METHODS—Resection specimens of UC and normal colon were analysed by immunomorphometry, immunoflow cytometry, and immunoelectron microscopy, using a large panel of monoclonal antibodies.
RESULTS—(1) In all cases of UC, colonic lamina propria contained numerous basal aggregates composed of lymphocytes, follicular dendritic cells, and CD80/B7.1 positive dendritic cells. (2) CD4+CD28 αβ T cells and B cells were the dominant cell types in the aggregates. (3) The aggregates contained a large fraction of cells that are normally associated with the epithelium: that is, γδ T cells (11 (7)%) and αEβ7+ cells (26 (13)%). The γδ T cells used Vδ1 and were CD4 CD8 . Immunoelectron microscopy analysis demonstrated TcR-γδ internalisation and surface downregulation, indicating that the γδ T cells were activated and engaged in the disease process. (4) One third of cells in the aggregates expressed the antiapoptotic protein bcl-2.
CONCLUSIONS—Basal lymphoid aggregates in UC colon are a consequence of anomalous lymphoid follicular hyperplasia, characterised by abnormal follicular architecture and unusual cell immunophenotypes. The aggregates increase in size with severity of disease, and contain large numbers of apoptosis resistant cells and activated mucosal γδ T cells. The latter probably colonise the aggregates as an immunoregulatory response to stressed lymphocytes or as a substitute for defective T helper cells in B cell activation. γδ T cells in the aggregates may be characteristic of UC.


Keywords: basal lymphoid aggregates; ulcerative colitis; T cell receptor γδ; immunomorphology

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Figure 1  .

Figure 1  

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Immunoperoxidase (A, B, C, D, F) and immunofluorescence (E) staining of basal lymphoid aggregates in ulcerative colitis colon. (A) Section stained with anti-CD45 monoclonal antibody (mAb). Three aggregates ("A") can be seen in the enlarged lamina propria (LP) in close proximity to the submucosa (SM). Large numbers of scattered CD45+ cells can also be seen in the lamina propria outside the aggregates. Several deep crypts ("C") extend into the lamina propria. The number of goblet cells is significantly reduced in cryptal and luminal epithelia ("E") (×18). (B) Section stained with a mixture of anti-pan TcR-γδ mAbs (TCRδ1, δTCS1, and Vδ1) showing several γδ T cells scattered throughout the aggregate. Inset: One γδ T cell with cytoplasmic staining and single cells with dotted staining (arrowhead) (×55, inset ×220). (C) Aggregate ("A") in a section stained with anti-αE/CD103 mAb. Cells with membrane staining are frequent. Arrows indicate strongly stained cells (×220). (D) Section stained with anti-CD28 mAb. CD28 expressing cells cannot be detected in the aggregates ("A") but are frequent in lamina propria (LP) outside the aggregates (arrows). Intraepithelial CD28+ cells are scarce (×32). (E) Section stained with anti-CD80 (B7.1) mAb. A dendritic cell network of CD80 positive cells in an aggregate ("A") is seen (×160). (F) Aggregate ("A") in a section stained with anti-bcl-2 mAb. A high proportion of the cells show cytoplasmic staining for the bcl-2 protein. Arrows indicate typical stained cells (×320). A, aggregate; C, crypt; E, luminal epithelium; LP, lamina propria; MM, muscularis mucosae; SM, submucosa.

Figure 2  .

Figure 2  

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Immunoperoxidase staining of sequential sections of basal lymphoid aggregates in ulcerative colitis colon (A, B, C) and of solitary follicles in normal colon (D, E, F). (A) Section stained with anti-CD3 mAb showing an aggregate with numerous positive cells concentrated in two main areas and a few scattered cells in the reciprocal B cell area. (B) The same aggregate as in (A) stained with a mixture of anti-CD19 mAb, anti-CD20 mAb, and anti-CD22 mAb. Positive cells are localised in the area with only a few scattered CD3+ cells. (C) The same aggregate as in (A) stained with anti-FDC mAb Ki-M4 showing a follicular dendritic cell network localised to the B cell area. (D) Section of a normal solitary follicle stained with anti-CD3 mAb. CD3+ cells are mainly found in three clusters localised in the outer rim of the follicle. (E) The same follicle as in (D) stained with a mixture of anti-CD19 mAb, anti-CD20 mAb, and anti-CD22 mAb. Positive cells are localised in the centre of the follicle. Note a central zone of large loosely packed positive cells surrounded by more tightly packed small positive cells. (F) The same follicle as in (D) stained with anti-FDC mAb Ki-M4 showing the follicular dendritic cell network localised to the centre of the B cell area. Original magnifications, A-F, ×55.

Figure 3  .

Figure 3  

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Immunomorphometric analysis of basal lymphoid aggregates in ulcerative colitis (UC) colon and solitary follicles in control colon. Bars represent mean (SD) per cent positive cells of all cells in the aggregate/follicle, as determined by morphometric counting of immunohistochemically stained cryosections. Nine UC colon samples (six severe, three moderate) were counted. Solitary follicles in 6-8 control colon samples were analysed for all markers except CD68, in which case n=2. An indirect immunoperoxidase technique was used for staining with anti-CD3, anti-TcR-αβ, anti-CD4, anti-CD8, anti-CD19/CD20/CD22, anti-CD57, anti-CD15, anti-CD14, and anti-CD68 monoclonal antibodies (mAb). Indirect immunofluorescence was used for staining with anti-TcR-γδ mAb. ***p<0.001, aggregates in UC compared with solitary follicles in control colon.

Figure 4  .

Figure 4  

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Flow cytometry analysis of high density lamina propria leucocytes isolated from one ulcerative colitis (UC) colon sample. Cells were stained with phycoerythrin labelled anti-pan-TcR-αβ monoclonal antibody (mAb) (BMA031) and with anti-Vδ1 mAb (δTCS1) for indirect immunofluorescence. The shaded histograms superimposed on the graphs show the negative controls. Expression of CD45R0 and CD45RA by T cells was assayed using PerCP labelled anti-CD3 mAb (SK7) and FITC labelled anti-CD45RA mAb (L28), and anti-CD45R0 mAb (UCHL-1), respectively. CD4 and CD8 positive cells were determined by two colour immunoflow cytometry using FITC labelled anti-CD4 mAb (MT310) and phycoerythrin labelled anti-CD8 mAb (DK25). Cells incubated with irrelevant fluorochrome conjugated mAbs served as negative controls and were used to determine the position of quadrant regions.

Figure 5  .

Figure 5  

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Immunoelectron micrographs of γδ T lymphocytes in normal colon. (A) A characteristic lamina propria γδ T cell showing homogeneous surface staining (arrows). (B) An intraepithelial γδ T cell showing diffuse surface staining (arrows). EC, epithelial cell. All ultrathin sections were examined without additional staining. Original magnification: A ×12 000; B ×11 500.

Figure 6  .

Figure 6  

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Immunoelectron micrographs of lamina propria (A-G) and intraepithelial (H) γδ T cells in ulcerative colitis colon. (A) Low power micrograph of a γδ T lymphocyte with numerous surface processes which are distinctly stained by the reaction product and concentrated at one pole of the cell (arrows). The rest of the cell surface is weakly stained. Inset: High magnification of the positively stained multivesicular body indicated by the arrowhead. (B) A γδ T cell showing the surface depositions of the reaction product which have the appearance of scarce clusters (arrows). One of the clusters is located over the surface flask-shaped invagination (arrowhead and in the inset at higher magnification). (C) A γδ T cell displaying the clustered reaction product on the cell surface (arrows) and numerous positively stained cytoplasmic vacuoles near the cell membrane (arrowheads). (D) A γδ T cell showing only numerous cytoplasmic vesicles and vacuoles of diverse sizes near the cell membrane and deep in the cell. The lumen of these structures exhibit variable intense staining by the reaction product (arrowheads). (E) A portion of the γδ T cell cytoplasm showing cytoplasmic vesicles that are connected with the plasma membrane and contain the reaction product (arrows). In addition, the cytoplasm contains numerous positively stained vacuoles (arrowheads). (F) A portion of the γδ T cell cytoplasm showing numerous multivesicular bodies mainly consisting of tightly packed positively stained microvesicles (arrowheads). Arrow depicts a small cluster of the reaction product on the cell surface. (G) A γδ T lymphocyte showing a strong positive staining of the cell surface (arrows) and the perinuclear space (large arrowheads). Small arrowheads indicate the positive staining of single cytoplasmic vacuoles. (H) A γδ T lymphocyte showing the positive staining of the cell surface (arrows) and perinuclear space (small arrowheads). Large arrowheads indicate the positively stained cisternal structure in the cytoplasm. EC, epithelial cell. All ultrathin sections were examined without additional staining. Original magnification: A ×8600, inset ×25 000; B ×9000, inset ×20 000; C ×8000; D ×9500; E ×29 500; F ×31 000; G ×10 000; H ×12 500. 

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