Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well characterized. We describe morphologic, phenotypic, genomic and clinical features of 3 cases of indolent primary small intestinal CD4+ T-cell lymphomas. All patients presented with diarrhea and weight loss and were diagnosed with celiac disease refractory to a gluten free diet at referring institutions. Small intestinal biopsies showed crypt hyperplasia, villous atrophy and a dense lamina propria infiltrate of small-sized CD4+ T-cells often with CD7 downregulation or loss. Gastric and colonic involvement was also detected (n = 2 each). Persistent, clonal TCRβ gene rearrangement products were detected at multiple sites. SNP array analysis showed relative genomic stability, early in disease course, and non-recurrent genetic abnormalities, but complex changes were seen at disease transformation (n = 1). Two patients are alive with persistent disease (4.6 and 2.5 years post-diagnosis), despite immunomodulatory therapy; one died due to bowel perforation related to large cell transformation 11 years post-diagnosis. Unique pathobiologic features warrant designation of indolent small intestinal CD4+ T-cell lymphoma as a distinct entity, greater awareness of which would avoid misdiagnosis as EATL or an inflammatory disorder, especially celiac disease.

Activation-induced cytidine deaminase (AID) is necessary for immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR) in T-dependent immune response in germinal centers (GCs). The structural similarity of AID with RNA-editing enzymes and its largely cytoplasmic location have fueled controversial views of its mode of interaction with DNA. We show that AID, a mature B-cell-restricted cytoplasmic antigen, is relocated into the nucleus in 2.5% of IntroductionThe host immune response to foreign antigens in higher vertebrates has evolved via separate cell lineages, such as immunoglobulin-producing B cells, effectors T cells, and a variety of accessory cells specialized in antigen processing and presentation (antigen-presenting cells, APCs). B cells can produce antigen-specific antibodies without (T independent, TI) or with (T dependent, TD) T-cell help. 1 The latter response is characterized by a process of progressive refinement of the antibody by selecting the type of immunoglobulin heavy chain (class switch recombination, CSR) and improving the affinity of the antigen-binding site (affinity maturation). This process entails genetic alterations of the DNA sequences of the immunoglobulin genes, excision of intervening heavy-chain sequences in CSR, and mutation of nucleotides in the antigen-binding region (somatic hypermutation, SHM), a process followed by selection and resulting in affinity maturation. SHM and CSR take place in a lymphoid structure called the germinal center (GC). Typically, cognate T-B interactions with APC and antigen occur at the border of primary lymphoid follicles. 2 Then, antigen-stimulated B cells enter the GC and experience a proliferative burst, mostly with unmutated Ig genes, [3][4][5] followed by the onset of SHM and CSR, resulting in clonal selection of class-switched B cells carrying multiple mutations of their high-affinity antibodies. 3,4,[6][7][8] Transit of GC centroblasts from the dark zone to the light zone of the GC may signal 2 different phases of the generation and selection of high-affinity Ig-carrying B cells. 9,10 The TI response in mice is typically extrafollicular, 11 unmutated, 12 and with no or short transit through a GC reaction. [13][14][15] Recently, evidence of hypermutated memory B cells without GC transit has been identified in humans 16,17 and mice. 14 The gene expression changes that occur from the initial activation up to the GC exit have been extensively described. [18][19][20] Genetic experiments have shown that activation-induced cytidine deaminase (AID) is essential for both CSR and SHM. 21 AID is a 24-kDa molecule of the APOBEC family, 22 restricted in its expression to lymphoid organs 22 and embryonic stem cells. 23 Two separate domains of the AID molecule are required for CSR and SHM, in cooperation with the DNA repair machinery. 24 The mechanism by which AID performs SHM and CSR has been a matter of controversy and is not yet resolved. The structural similarity with the APOBEC family, an RNA-editing enzyme group of proteins, and ot...

The transit of T cell-activated B cells through the germinal center (GC) is controlled by sequential activation and repression of key transcription factors, executing the pre- and post-GC B cell program. B cell lymphoma (BCL) 6 and IFN regulatory factor (IRF) 8 are necessary for GC formation and for its molecular activity in Pax5+PU.1+ B cells. IRF4, which is highly expressed in BCL6− GC B cells, is necessary for class switch recombination and the plasma cell differentiation at exit from the GC. In this study, we show at the single-cell level broad coexpression of IRF4 with BCL6, Pax5, IRF8, and PU.1 in pre- and post-GC B cells in human and mouse. IRF4 is down-regulated in BCL6+ human GC founder cells (IgD+CD38+), is absent in GC centroblasts, and is re-expressed in positive regulatory domain 1-positive centrocytes, which are negative for all the B cell transcription factors. Activated (CD30+) and activation-induced cytidine deaminase-positive extrafollicular blasts coexpress Pax5 and IRF4. PU.1-negative plasma cells and CD30+ blasts uniquely display the conformational epitope of IRF4 recognized by the MUM1 Ab, an epitope that is absent from any other IRF4+PU.1+ lymphoid and hemopoietic subsets. Low grade B cell lymphomas, representing the malignant counterpart of pre- and post-GC B cells, accordingly express IRF4. However, a fraction of BCL6+ diffuse large B cell lymphomas express IRF4 bearing the MUM1 epitope, indicative of a posttranscriptional modification of IRF4 not seen in the normal counterpart.