Differential Expression Of Chemokine Receptors Research Articles

Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID

Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.

Differential expression of chemokine receptors on monocytes in TB and HIV S

In the present study, we defined multiple chemokine receptors expressed by classical, intermediate and non-classical monocyte subsets in TB, HIV and TB/HIV co-infection and associate it with the perturbation of monocyte subsets due to the diseases. Peripheral blood mononuclear cells from TB+ (n = 34), HIV+ (n = 35), TB + HIV+ (n = 12), as well as TB-HIV- healthy controls (n = 39), were tested for monocyte phenotyping by flow cytometry. Frequencies of intermediate and non-classical monocytes were significantly higher in TB and/or HIV disease relative to healthy controls. CCR2 and CX3CR1 were significantly higher on monocytes in TB disease, whereas CCR4 and CCR5 were present at higher levels in HIV disease. TB/HIV co-infected patients exhibited CCR2, CCR5 and CX3CR1 levels intermediate to TB and HIV subjects, while CCR4 was at a higher level than HIV. Despite the increase in the expression of chemokine receptors due to disease conditions, chemokine receptors maintained their original expression pattern on monocyte subsets. Our data provided new insight into the disease-specific but not monocyte subsets-specific modulation of chemokine receptors in TB and HIV.

Chemokine receptors differentially expressed by race category and molecular subtype in the breast cancer TCGA cohort

Racial disparities in mortality due to metastasis remain significant among breast cancer patients. Chemokine receptors contribute to breast tumors and metastatic outcome. We explored for significant differences in chemokine receptor expression in breast tumors from Black, Asian, and White patients in The Cancer Genome Atlas. We show that despite sharing the same molecular subtype, expression of the chemokine receptors ACKR1, CCR3, CCR6, CCRL1, CCRL2, CXCR1, CXCR2, CXCR4, CXCR6, and CXC3CR1 was significantly different depending on racial group. For patients with triple negative breast cancer, CCR3 was higher in Black versus White and CCRL2 was higher in Asian versus White. In luminal A tumors, ACKR1 was lower in Asian versus White, CCR3 was higher in Black versus White, and CCR6 and CXC3CR1 were lower in Black versus White. In luminal B tumors, CCRL2 was lower in Black versus White, CXCR1 and CXC3CR1 were lower in Asian versus White, and CXCR2 was lower in Black and Asian versus White. In HER2 enriched tumors, CCR3 was higher in Black versus White and CXCR4 lower in Asian versus White. CCR3, CCR6, and CXCR6 associated with worse patient survival. These findings can inform improved treatment strategies to decrease racial disparities in breast cancer burden.

Sex differences in M2 polarization, chemokine and IL-4 receptors in monocytes and macrophages from asthmatics

Allergic asthma affects more women than men. It is mediated partially by IL-4/IL-13-driven polarization of monocyte-derived macrophages in the lung. We tested whether sex differences in asthma are due to differential IL-4 responsiveness and/or chemokine receptor expression in monocytes and monocyte-derived macrophages from healthy and allergic asthmatic men and women. We found female cells expressed M2 genes more robustly following IL-4 stimulation than male cells, as did cells from asthmatics than those from healthy controls. This likely resulted from increased expression ofγC, part of the type I IL-4 receptor, and reduced IL-4–induced SOCS1, a negative regulator of IL-4 signaling, in asthmatic compared to healthy macrophages. Monocytes from asthmatic women expressed more CX3CR1, which enhances macrophage survival. Our findings highlight how sex differences in IL-4 responsiveness and chemokine receptor expression may affect monocyte recruitment and macrophage polarization in asthma, potentially leading to new sex-specific therapies to manage the disease.

Innate-like Chemokine Receptor Profile and Migratory Behaviour By Terminally Differentiated and Educated NK Cells

Natural Killer (NK) cells play an essential role in cancer surveillance and have a unique capability of spontaneous cytotoxicity against cancer cells. The human NK cell repertoire is functionally diversified through a tightly regulated differentiation process characterized by an early transition from CD56bright to CD56dim NK cells, followed by coordinated changes in expression of inhibitory receptors, including NKG2A and killer cell immunoglobulin-like receptors (KIR). The acquisition of self HLA class I binding KIRs during NK cell differentiation tunes the cytotoxic potential of NK cells in a process termed education, characterized by increased loading of granzyme B in dense core granules. Although NK cell differentiation and education are critical determinants of the functional potential of the cell, little is known about how these events shape the migratory behavior of NK cells. To mediate appropriate and directed immune response against cancer, NK cells must be capable of migration to the tumor site. This process is mediated by chemokines, which guide cell migration by binding to their specific receptors. For example, in multiple myeloma, CXCR3 and CCR5 ligands (MIG, IP-10, and MIP-1a) are significantly upregulated in the bone marrow compared to healthy controls, affecting the composition of immune cells in the tumor microenvironment. In order to delineate the homing patterns of distinct NK cell subsets, we used high-dimensional flow cytometry combined with functional assays to map the NK cell chemokine receptor expression and migratory behavior. We screened resting and cytokine/feeder cell stimulated peripheral blood NK cells for the expression of a panel of 20 chemokine receptors (A). Based on CD56, CD57, NKG2A, and KIR expression, NK cells were divided into 6 phenotypically and functionally distinct subsets that were ordered according to their differentiation status (B). We found that the expression of CX3CR1, CXCR1, CXCR2, and CMKLR1 gradually increased during differentiation, whereas the expression of CXCR3, CCR7, and CCR5 was lower in more differentiated NK cells. CXCR4, CCR4, and CCR2 expression was relatively uniform across all subsets. Interestingly, CCR1 and CXCR6 were expressed mainly on less differentiated NKG2A+ CD56dim NK cells (B). Next, we stratified the chemokine receptor expression on mature KIR+ NK cells based on the expression of self (educated) or non-self KIR (uneducated). Educated NK cells expressed CXCR1, CX3CR1, CCR5, and CMKLR1 at higher levels than the uneducated NK cells. Conversely, CXCR3 was expressed at lower levels on educated NK cells (C). No difference was observed for CXCR2 expression. To determine whether the observed differences in chemokine receptor expression translate into altered chemokine responsiveness between the subsets, we combined the transwell system with multicolor flow cytometry. We found that the chemokine-induced migration capability of NK cells correlated closely with the expression level of corresponding chemokine receptor, leading to subset specific responses to various chemokine gradients (D). The present results show that peripheral blood NK cell chemokine receptor profile changes in a coordinated fashion during NK cell differentiation and is further influenced by the expression of self-specific KIR. Interestingly, receptors which expression declines during NK cell differentiation (CCR5, CCR7, and CXCR3) are commonly associated with adaptive T cell responses to viruses, whereas receptors that are upregulated along the differentiation axis (CXCR1, CXCR2, CX3CR1, CMKLR1) are typical for neutrophils and macrophages as a part of the innate immune response. Thus, our results suggest that NK cell differentiation and education processes together shape the NK cell migratory capabilities to promote homing of the most functional NK cell subsets to the site of inflammation and serve as the first line of defense in the immune response to pathogens and tumors. Figure Disclosures Malmberg: Fate Therapeutics: Consultancy, Patents & Royalties; Vycellix: Membership on an entity's Board of Directors or advisory committees.

Transcriptomic Profiling of Human Effector and Regulatory T Cell Subsets Identifies Predictive Population Signatures.

After activation, CD4+ Th cells differentiate into functionally specialized populations that coordinate distinct immune responses and protect against different types of pathogens. In humans, these effector and memory Th cell subsets can be readily identified in peripheral blood based on their differential expression of chemokine receptors that govern their homeostatic and inflammatory trafficking. Foxp3+ regulatory T (Treg) cells can also be divided into subsets that phenotypically mirror each of these effector populations and share expression of key transcription factors and effector cytokines. In this study, we performed comprehensive transcriptional profiling of 11 phenotypically distinct Th and Treg cell subsets sorted from peripheral blood of healthy individuals. Despite their shared phenotypes, we found that mirror Th and Treg subsets were transcriptionally dissimilar and that Treg cell populations showed limited transcriptional diversity compared with Th cells. We identified core transcriptional signatures shared across all Th and Treg cell populations and unique signatures that define each of the Th or Treg populations. Finally, we applied these signatures to bulk Th and Treg RNA-sequencing data and found enrichment of specific Th and Treg cell populations in different human tissues. These results further define the molecular basis for the functional specialization and differentiation of Th and Treg cell populations and provide a new resource for examining Th and Treg specialization in RNA-sequencing data.

Dendritic Cells and Microglia Have Non-redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

SummaryBrain CD11c+ cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c+ cells, but their phenotype, origin, and functions remain largely unknown. We report that, after cerebral ischemia, microglia attract DCs to the inflamed brain, and astroglia produce Flt3 ligand, supporting development and expansion of CD11c+ cells. CD11c+ cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L+ conventional cDC2, and also cDC1, plasmacytoid, and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c+ microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c− and CD11c+ microglia in the capacity to present antigen through MHCI and MHCII. Of note, cDC1s protect from brain injury after ischemia. We thus reveal aspects of the dynamics and functions of brain DCs in the regulation of inflammation and immunity.

Dendritic Cells and Microglia Have Non-Redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

Brain CD11c+ cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c+ cells but their phenotype, origin, and functions remain largely unknown. We report that after cerebral ischemia, microglia attract DCs to the inflamed brain and astroglia produce Flt3 ligand supporting development and expansion of CD11c+ cells. CD11c+ cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L+ conventional cDC2, and also cDC1, plasmacytoid and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c+ microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c- and CD11c+ microglia in the capacity to present antigen through MHC I and MHC II. Of note, cDC1s protect from brain injury after ischemia. We thus reveal novel aspects of the dynamics and functions of brain DCs in regulation of inflammation and immunity.

Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells

Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells

Differential chemokine receptor expression and usage by pre-cDC1 and pre-cDC2.

Conventional dendritic cells (cDCs) are continuously replenished by bone marrow-derived precursors called pre-DCs, which traffic through the blood to peripheral tissues. Pre-DCs are a heterogeneous population that includes cDC subset-committed progenitors, namely pre-cDC1 and pre-cDC2, which give rise to mature cDC1 and cDC2, respectively. Regulation of pre-DC subset trafficking is thought to aid the host response to immune challenge. However, the molecular cues regulating pre-cDC1 versus pre-cDC2 trafficking toward peripheral sites during homeostasis and disease remain elusive. Here, we report that pre-cDC1 but not pre-cDC2 express the T helper type 1-associated chemokine receptor CXCR3. Moreover, we identify a cell-intrinsic role for CXCR3 in the trafficking of pre-cDC1 to melanoma tumors but not to non-inflamed organs. We also show that tumor cDC1 numbers can be increased pharmacologically by targeting dipeptidyl peptidase-4 (CD26), a negative regulator of CXCR3 ligands. Our findings demonstrate that pre-cDC1 trafficking is regulated distinctly from pre-cDC2, which is relevant for our understanding of the DC lineage in the context of cancer and inflammation.

Follicular CD8+ T Cells: Origin, Function and Importance during HIV Infection.

The lymphoid follicle is critical for the development of humoral immune responses. Cell circulation to this site is highly regulated by the differential expression of chemokine receptors. This feature contributes to the establishment of viral reservoirs in lymphoid follicles and the development of some types of malignancies that are able to evade immune surveillance, especially conventional CD8+ T cells. Interestingly, a subtype of CD8+ T cells located within the lymphoid follicle (follicular CD8+ T cells) was recently described; these cells have been proposed to play an important role in viral and tumor control, as well as to modulate humoral and T follicular helper cell responses. In this review, we summarize the knowledge on this novel CD8+ T cell population, its origin, function, and potential role in health and disease, in particular, in the context of the infection by the human immunodeficiency virus.

Differences between chronic lymphocytic leukaemia and small lymphocytic lymphoma cells by proteomic profiling and SNP microarray analysis

The majority of malignant cells in chronic lymphocytic leukaemia (CLL) circulate in the peripheral blood whereas small lymphocytic lymphoma (SLL) cells reside in tissues. The aim of this study was to detect differences in chemokine receptor expression, DNA single nucleotide polymorphism (SNP) microarray analysis and proteomic profiling to help elucidate why the cells remain in their respective environments. We identified by flow cytometric studies of chemokine receptors and DNA SNP microarray analysis significant differences between cells from CLL and SLL patients. Proteomic analysis revealed two potential markers (m/z 3091 and 8707) to distinguish the two disorders. There was a significantly greater expression of leucocyte trafficking receptor CXCR3 (CD183) and migration and homing receptor CXCR4 (CD184), and significantly lower expression of cell adhesion molecule integrin α4 chain (CD49d), on CLL cells, compared with SLL cells. Conversely, SNP microarrays revealed greater numbers of copy-neutral loss of heterozygosity chromosomal aberrations, as well as gross chromosomal aberrations, in the SLL group, compared with the CLL group. These findings revealed that there was a significantly greater expression of trafficking, migration and homing receptors and significantly lower expression of adhesion molecules on CLL cells than on SLL cells, and that SLL may be a more progressive disease than CLL, with a more complex genotype.

Differential somatostatin and CXCR4 chemokine receptor expression in MALT-type lymphoma of gastric and extragastric origin

Whereas the different somatostatin receptor (SSTR) subtypes and the chemokine receptor CXCR4 are known to be expressed in a wide variety of human malignancies, comprehensive data are still lacking for MALT-type lymphomas. Overall, 55 cases of MALT-type lymphoma of both gastric and extragastric origin were evaluated for the SSTR subtype and CXCR4 expression by means of immunohistochemistry using novel monoclonal rabbit antibodies. The stainings were rated by means of the immunoreactive score and correlated with clinical data. While the CXCR4 was detected in 92% of the cases investigated, the SSTR subtypes were much less frequently present. The SSTR5 was expressed in about 50% of the cases, followed by the SSTR3, the SSTR2A, the SSTR4 and the SSTR1, which were present in 35, 27, 18 or 2%, respectively, of the tumors only. Gastric lymphomas displayed a significantly higher SSTR3, SSTR4 and SSTR5 expression than extragastric tumors. A correlation between CXCR4 and Ki-67 expression was seen in gastric lymphomas, whereas primarily in extragastric tumors SSTR5 negativity was associated with poor patient outcome. The CXCR4 may serve as a promising target for diagnostics and therapy of MALT-type lymphomas, while the SSTRs appear not suitable in this respect.

Efferocytosis as a regulator of macrophage chemokine receptor expression and polarization.

Efferocytosis has been suggested to promote macrophage resolution programs that are dependent on motility and emigration, however, few studies have addressed directed migration in resolving macrophages. In this report, we hypothesized that efferocytosis would induce differential chemokine receptor expression. Polarized macrophage populations, including macrophages actively engaged in efferocytosis, were characterized by PCR array and traditional transwell motility assays. We identified specific up-regulation of chemokine receptor CXCR4 on both mouse and human macrophages and characterized in vivo expression of CXCR4 in a resolving model of murine peritonitis. Using adoptive transfer and AMD3100 blocking, we confirmed a role for CXCR4 in macrophage egress to draining lymphatics. Collectively these data provide an important mechanistic link between efferocytosis and macrophage emigration.

CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis.

IntroductionPatients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA+ RA and differences in treatment outcome between these subpopulations suggest that ACPA+ and ACPA− RA are different disease subsets. The identification of T-helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA+ RA. In this context we recently identified a potential pathogenic role for CCR6+ Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status.MethodsWe performed a nested matched case–control study including 27 ACPA+ and 27 ACPA− treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4+CD45RO+ (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration.ResultsACPA status was not related to differences in total CD4+ T cell or memory Th cell proportions. However, ACPA+ patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4+ and CCR10+ Th cells were found. Within the CCR6+ cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4+CCR10−), Th17.1 (CXCR3+), Th22 (CCR4+CCR10+) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA+ patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6−CXCR3+; p = 0.90), Th2 (CCR6−CCR4+; p = 0.27) and T-regulatory (CD25hiFOXP3+; p = 0.06) cell proportions. Interestingly, CCR6+ Th cells were inversely correlated with disease duration in ACPA− patients (R2 = −0.35; p < 0.01) but not in ACPA+ (R2 < 0.01; p = 0.94) patients.ConclusionsThese findings demonstrate that increased peripheral blood CCR6+ Th cells proportions distinguish ACPA+ RA from ACPA− RA. This suggests that CCR6+ Th cells are involved in the differences in disease severity and treatment outcome between ACPA+ and ACPA− RA.

The Differential Expression and Function of the Inflammatory Chemokine Receptor CXCR5 in Benign Prostatic Hyperplasia and Prostate Cancer.

Background: Chemokine and chemokine receptors could have played an important role in tumor angiogenesis and distant metastasis. The mechanism of inflammation, expression and function of chemokines and chemokine receptors in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remain unclear. The purpose of present study is to detect differential expression and function of chemokines and chemokine receptors (CCRs) in BPH and PCa.Methods: BPH-1 and peripheral blood mononuclear cells (PBMCs) were co-cultured in Transwell chambers, and human normal prostate (NP) tissues, BPH tissues and PCa tissues were collected. CCR gene-chips were used to analyze and compare the differential expression of CCRs in BPH-1 cells, BPH-1 cells co-cultured with PBMCs, and LNCaP cells. The differential expression of CCRs was detected and validated using real-time PCR, western blotting and immunofluorescence (IF). The proliferation of LNCaP cells was also investigated after the knockdown CXCR5.Results: Results of gene-chips indicated that there was low or no expression of CCR10, CXCR1, CXCR3 and CXCR5 in BPH-1 cells, whereas the expression of these receptors in BPH-1 cells was increased by PBMCs, and the expression was high in LNCaP cells. Furthermore, real-time PCR and western blotting confirmed the above mentioned results. IF verified no or low expression of CXCR1, CXCR3 and CXCR5 in NP tissues, low or moderate expression in BPH and high expression in PCa. However, CCR10 was not expressed at detectable levels in the three groups. The growth and proliferation of LNCaP cells was markedly inhibited after down-regulation of CXCR5.Conclusions: PCa cells expressed high levels of CCR10, CXCR1, CXCR3 and CXCR5. Although BPH cells did not express these factors, their expression was up-regulated when BPH-1 cells were incubated with inflammatory cells. Finally, down-regulation of CXCR5 inhibited the growth and proliferation of LNCaP cells.

The oral commensal Streptococcus mitis shows a mixed memory Th cell signature that is similar to and cross-reactive with Streptococcus pneumoniae.

BackgroundCarriage of and infection with Streptococcus pneumoniae is known to predominantly induce T helper 17 (Th17) responses in humans, but the types of Th cells showing reactivity towards commensal streptococci with low pathogenic potential, such as the oral commensals S. mitis and S. salivarius, remain uncharacterized.MethodsMemory CD4+ T helper (Th) cell subsets were isolated from healthy human blood donors according to differential expression of chemokine receptors, expanded in vitro using polyclonal stimuli and characterized for reactivity against different streptococcal strains.ResultsTh cells responding to S. mitis, S. salivarius and S. pneumoniae were predominantly in a CCR6+CXCR3+ subset and produced IFN-γ, and in a CCR6+CCR4+ subset and produced IL-17 and IL-22. Frequencies of S. pneumoniae-reactive Th cells were higher than frequencies of S. mitis- and S. salivarius-specific Th cells. S. mitis and S. pneumoniae isogenic capsule knock-out mutants and a S. mitis mutant expressing the serotype 4 capsule of S. pneumoniae showed no different Th cell responses as compared to wild type strains. S. mitis-specific Th17 cells showed cross-reactivity with S. pneumoniae.ConclusionsAs Th17 cells partly control clearance of S. pneumoniae, cross-reactive Th17 cells that may be induced by commensal bacterial species may influence the immune response, independent of capsule expression.

Differential Expression of Chemokines, Chemokine Receptors and Proteinases by Foreign Body Giant Cells (FBGCs) and Osteoclasts

Osteoclasts and foreign body giant cells (FBGCs) are both derived from the fusion of macropahges. These cells are seen in close proximity during foreign body reactions, therefore it was assumed that they might interact with each other. The aim was to identify important genes that are expressed by osteoclasts and FBGCs which can be used to understand peri-implantitis and predict the relationship of these cells during foreign body reactions. Bone marrow macrophages (BMM) were treated with receptor activator of nuclear factor kappa B ligand (RANKL) to produce osteoclasts. Quantitative PCR (qPCR) was used to identify the genes that were expressed by osteoclasts and FBGCs compared to macrophage controls. TRAP staining was used to visualise the cells while gelatine zymography and western blots were used for protein expression. Tartrate-resistant acid phosphatase (TRAP), matrix metallo proteinase 9 (MMP9), nuclear factor of activated T cells 1 (NFATc1), cathepsin K (CTSK) and RANK were significantly lower in FBGCs compared to osteoclasts. Inflammation specific chemokines such as monocyte chemotactic protein (MCP1 also called CCL2), macrophage inflammatory protein 1 alpha (MIP1α), MIP1β and MIP1γ, and their receptors CCR1, CCR3 and CCR5, were highly expressed by FBGCs. FBGCs were negative for osteoclast specific markers (RANK, NFATc1, CTSK). FBGCs expressed chemokines such as CCL2, 3, 5 and 9 while osteoclasts expressed the receptors for these chemokines i.e. CCR1, 2 and 3. Our findings show that osteoclast specific genes are not expressed by FBGCs and that FBGCs interact with osteoclasts during foreign body reaction through chemokines.

Altered natural killer cell subset homeostasis and defective chemotactic responses in paroxysmal nocturnal hemoglobinuria

AbstractIn paroxysmal nocturnal hemoglobinuria (PNH), hematopoietic cells lacking glycosylphosphatidylinositol (GPI)-linked proteins on their surface (GPIneg) exist alongside normal (GPI+) cells. Analysis of natural killer (NK) cell subsets in 47 PNH patients revealed that the ratio of CD56bright:CD56dim NK cells differed in the GPI+ and GPIneg populations, with GPInegCD56bright NK cells significantly more abundant in peripheral blood than their normal GPI+ counterparts. Indeed, GPI+CD56bright NK cells were not detected in the peripheral blood of some patients, suggesting their trafficking to a niche unavailable to the GPInegCD56bright NK cell population. Defective cellular trafficking in this disease was supported by findings showing differential chemokine receptor expression between GPI+ and GPIneg NK cells and impaired stromal cell–derived factor 1 (SDF-1)–induced chemotaxis of GPIneg NK cells. Our results indicate a role for GPI-linked proteins in NK cell subset homeostasis and suggest that differential chemokine responses might contribute to the balance of GPI+ and GPIneg populations in this disease.

Small Lymphocytic Lymphoma and Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by peripheral blood B-cell lymphocytosis as well as lymphadenopathy, organomegaly, cytopenias, and systemic symptoms. Chronic lymphocytic leukemia cells have a distinctive immunophenotype, and the disease has a characteristic pattern of histological infiltration in the lymph node and bone marrow. The clinical course of CLL is heterogeneous, with some patients presenting with very indolent disease and other patients having a more aggressive malignancy. It is known that genetic abnormalities underlie this difference in clinical presentation. Some patients may present solely with lymphadenopathy, organomegaly, and presence of infiltrating monoclonal B cells with the same immunophenotype as CLL cells, but lacking peripheral blood lymphocytosis. This disease is called small lymphocytic lymphoma (SLL) and has been considered for almost 2 decades to be the tissue equivalent of CLL. Both CLL and SLL are currently considered different manifestations of the same entity by the fourth edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. It is suspected that differential expression of chemokine receptors (e.g., reduced expression of R1 and CCR3 in SLL cells), integrins (e.g., CLL cells have lower expression of integrin αLβ2), and genetic abnormalities (a higher incidence of trisomy 12 and lower incidence of del(13q) is found in SLL) may explain some of the clinical differences between these 2 disorders. However, there is still a lack of knowledge on the precise biological basis underlying the different clinical presentations of CLL and SLL. It is expected that future studies will shed light on the pathophysiology of both disorders.