-
Mirjam Schenk,
Stephan R Krutzik,
Peter A Sieling,
Delphine J Lee,
Rosane M B Teles, Maria Teresa Ochoa,
Evangelia Komisopoulou,
Euzenir N Sarno,
Thomas H Rea,
Thomas G Graeber,
Soohyun Kim,
Genhong Cheng,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.
Nature medicine 03/2012; 18(4):555-63. · 27.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Many physicians in the United States and other nonendemic countries lack familiarity with New World cutaneous leishmaniasis (CL) and fail to include it in their differential diagnosis when seeing patients with suggestive lesions and recent high-risk travel. Moreover, even when the diagnosis of New World CL is considered and confirmed, physicians in the United States still face obstacles in obtaining appropriate treatment. In this report, we present 3 cases of New World CL that were either initially misdiagnosed or faced significant delays in therapy. We also discuss the optimal approach by which to confirm New World CL and to collaborate with professional colleagues at the Centers for Disease Control and Prevention in treating individual patients. In particular, when pentavalent antimonial treatment is needed for treatment, physicians must obtain appropriate diagnostic studies, communicate with experts at the Centers for Disease Control and Prevention, complete necessary paperwork, and obtain approval from their local institutional review board to administer it.
Journal of the American Academy of Dermatology 03/2011; 64(3):587-92. · 3.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The Leishmaniases are a group of diseases transmitted to humans by the bite of a sandfly, caused by protozoan parasites of the genus Leishmania. Various Leishmania species infect humans, producing a spectrum of clinical manifestations. It is estimated that 350 million people are at risk, with a global yearly incidence of 1-1.5 million for cutaneous and 500,000 for visceral Leishmaniasis (VL). VL is a major cause of morbidity and mortality in East Africa, Brazil and the Indian subcontinent. Co-infection with human immunodeficiency virus (HIV) alters the immune response to the disease. Here we review the immune response to Leishmania in the setting of HIV co-infection. Improved understanding of the immunology involved in co-infections may help in designing prophylactic and therapeutic strategies against Leishmaniasis.
Journal of global infectious diseases 09/2010; 2(3):248-57.
-
Antoni Ribas,
Begoña Comin-Anduix,
Bartosz Chmielowski,
Jason Jalil,
Pilar de la Rocha,
Tara A McCannel, Maria Teresa Ochoa,
Elizabeth Seja,
Arturo Villanueva,
Denise K Oseguera,
Bradley R Straatsma,
Alistair J Cochran,
John A Glaspy,
Liu Hui,
Francesco M Marincola,
Ena Wang,
James S Economou,
Jesus Gomez-Navarro
[show abstract]
[hide abstract]
ABSTRACT: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma.
Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point.
Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response.
The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.
Clinical Cancer Research 10/2009; 15(19):6267-76. · 7.74 Impact Factor
-
Dennis Montoya,
Daniel Cruz,
Rosane M B Teles,
Delphine J Lee, Maria Teresa Ochoa,
Stephan R Krutzik,
Rene Chun,
Mirjam Schenk,
Xiaoran Zhang,
Benjamin G Ferguson,
Anne E Burdick,
Euzenir N Sarno,
Thomas H Rea,
Martin Hewison,
John S Adams,
Genhong Cheng,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. We investigated the regulation of these key functions in human blood-derived macrophages. Interleukin-10 (IL-10) induced the phagocytic pathway, including the C-type lectin CD209 and scavenger receptors, resulting in phagocytosis of mycobacteria and oxidized low-density lipoprotein. IL-15 induced the vitamin D-dependent antimicrobial pathway and CD209, yet the cells were less phagocytic. The differential regulation of macrophage functional programs was confirmed by analysis of leprosy lesions: the macrophage phagocytosis pathway was prominent in the clinically progressive, multibacillary form of the disease, whereas the vitamin D-dependent antimicrobial pathway predominated in the self-limited form and in patients undergoing reversal reactions from the multibacillary to the self-limited form. These data indicate that macrophage programs for phagocytosis and antimicrobial responses are distinct and differentially regulated in innate immunity to bacterial infections.
Cell host & microbe 10/2009; 6(4):343-53. · 13.02 Impact Factor
-
Daniel Cruz,
Andrew D Watson,
Christopher S Miller,
Dennis Montoya, Maria-Teresa Ochoa,
Peter A Sieling,
Miguel A Gutierrez,
Mohamad Navab,
Srinivasa T Reddy,
Joseph L Witztum,
Alan M Fogelman,
Thomas H Rea,
David Eisenberg,
Judith Berliner,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: Intracellular pathogens survive by evading the host immune system and accessing host metabolic pathways to obtain nutrients for their growth. Mycobacterium leprae, the causative agent of leprosy, is thought to be the mycobacterium most dependent on host metabolic pathways, including host-derived lipids. Although fatty acids and phospholipids accumulate in the lesions of individuals with the lepromatous (also known as disseminated) form of human leprosy (L-lep), the origin and significance of these lipids remains unclear. Here we show that in human L-lep lesions, there was preferential expression of host lipid metabolism genes, including a group of phospholipases, and that these genes were virtually absent from the mycobacterial genome. Host-derived oxidized phospholipids were detected in macrophages within L-lep lesions, and 1 specific oxidized phospholipid, 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphorylcholine (PEIPC), accumulated in macrophages infected with live mycobacteria. Mycobacterial infection and host-derived oxidized phospholipids both inhibited innate immune responses, and this inhibition was reversed by the addition of normal HDL, a scavenger of oxidized phospholipids, but not by HDL from patients with L-lep. The accumulation of host-derived oxidized phospholipids in L-lep lesions is strikingly similar to observations in atherosclerosis, which suggests that the link between host lipid metabolism and innate immunity contributes to the pathogenesis of both microbial infection and metabolic disease.
Journal of Clinical Investigation 08/2008; 118(8):2917-28. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A key cell type of the resident skin immune system is the dendritic cell (DC), which in normal skin is located in two distinct microanatomical compartments: Langerhans cells (LCs), mainly in the epidermis, and dermal DCs (DDCs), in the dermis. Here, the lineage of DDCs was investigated using monoclonal antibodies and immunohistology. We provide evidence that "DDC" comprise at least two major phenotypic populations of dendritic-appearing cells, immature DC expressing CD1, CD11c and CD208; and macrophages expressing CD209, CD206, CD163, and CD68. These data suggest that dermal dendritic-appearing macrophages comprise a novel part of the innate immune response in the resident skin immune system.
Journal of Investigative Dermatology 04/2008; 128(9):2225-31. · 6.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The differentiation of monocytes into dendritic cells (DC) is a key mechanism by which the innate immune system instructs the adaptive T cell response. In this study, we investigated whether leukocyte Ig-like receptor A2 (LILRA2) regulates DC differentiation by using leprosy as a model. LILRA2 protein expression was increased in the lesions of the progressive, lepromatous form vs the self-limited, tuberculoid form of leprosy. Double immunolabeling revealed LILRA2 expression on CD14+, CD68+ monocytes/macrophages. Activation of LILRA2 on peripheral blood monocytes impaired GM-CSF induced differentiation into immature DC, as evidenced by reduced expression of DC markers (MHC class II, CD1b, CD40, and CD206), but not macrophage markers (CD209 and CD14). Furthermore, LILRA2 activation abrogated Ag presentation to both CD1b- and MHC class II-restricted, Mycobacterium leprae-reactive T cells derived from leprosy patients, while cytokine profiles of LILRA2-activated monocytes demonstrated an increase in TNF-alpha, IL-6, IL-8, IL-12, and IL-10, but little effect on TGF-beta. Therefore, LILRA2 activation, by altering GM-CSF-induced monocyte differentiation into immature DC, provides a mechanism for down-regulating the ability of the innate immune system to activate the adaptive T cell response while promoting an inflammatory response.
The Journal of Immunology 01/2008; 179(12):8128-36. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Distinct CD4(+) T-cell epitopes within the same protein can be optimally processed and loaded into major histocompatibility complex (MHC) class II molecules in disparate endosomal compartments. The CD1 protein isoforms traffic to these same endosomal compartments as directed by unique cytoplasmic tail sequences, therefore we reasoned that antigen/CD1 chimeras containing the different CD1 cytoplasmic tail sequences could optimally target antigens to the MHC class II antigen presentation pathway. Evaluation of trafficking patterns revealed that all four human CD1-derived targeting sequences delivered antigen to the MHC class II antigen presentation pathway, to early/recycling, early/sorting and late endosomes/lysosomes. There was a preferential requirement for different CD1 targeting sequences for the optimal presentation of an MHC class II epitope in the following hierarchy: CD1b > CD1d = CD1c > > > CD1a or untargeted antigen. Therefore, the substitution of the CD1 ectodomain with heterologous proteins results in their traffic to distinct intracellular locations that intersect with MHC class II and this differential distribution leads to specific functional outcomes with respect to MHC class II antigen presentation. These findings may have implications in designing DNA vaccines, providing a greater variety of tools to generate T-cell responses against microbial pathogens or tumours.
Immunology 12/2007; 122(4):522-31. · 3.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We investigated the regulation of T-cell homing receptors in infectious disease by evaluating the cutaneous lymphocyte antigen (CLA) in human leprosy. We found that CLA-positive cells were enriched in the infectious lesions associated with restricting the growth of the pathogen Mycobacterium leprae, as assessed by the clinical course of infection. Moreover, CLA expression on T cells isolated from the peripheral blood of antigen-responsive tuberculoid leprosy patients increased in the presence of M. leprae (2.4-fold median increase; range 0.8-6.1, n = 17), but not in unresponsive lepromatous leprosy patients (1.0-fold median increase; range 0.1-2.2, n = 10; P < 0.005). Mycobacterium leprae specifically up-regulated the skin homing receptor, CLA, but not alpha(4)/beta(7), the intestinal homing receptor, which decreased on T cells of patients with tuberculoid leprosy after antigen stimulation (2.2-fold median decrease; range 1.6-3.4, n = 3). Our data indicate that CLA expression is regulated during the course of leprosy infection and suggest that T-cell responsiveness to a microbial antigen directs antigen-specific T cells to the site of infection.
Immunology 04/2007; 120(4):518-25. · 3.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human infection with Mycobacterium leprae, an intracellular bacterium, presents as a clinical and immunological spectrum; thus leprosy provides an opportunity to investigate mechanisms of T-cell responsiveness to a microbial pathogen. Analysis of the T-cell receptor (TCR) repertoire in leprosy lesions revealed that TCR BV6(+) T cells containing a conserved CDR3 motif are over-represented in lesions from patients with the localized form of the disease. Here, we derived a T-cell clone from a leprosy lesion that expressed TCR BV6 and the conserved CDR3 sequence L-S-G. This T-cell clone produced a T helper type 1 cytokine pattern, directly lysed M. leprae-pulsed antigen-presenting cells by the granule exocytosis pathway, and expressed the antimicrobial protein granulysin. BV6(+) T cells may therefore functionally contribute to the cell-mediated immune response against M. leprae.
Immunology 04/2007; 120(3):354-61. · 3.32 Impact Factor
-
Belinda H Tan,
Christoph Meinken,
Max Bastian,
Heiko Bruns,
Annaliza Legaspi, Maria Teresa Ochoa,
Stephan R Krutzik,
Barry R Bloom,
Tomas Ganz,
Robert L Modlin,
Steffen Stenger
[show abstract]
[hide abstract]
ABSTRACT: A key target of many intracellular pathogens is the macrophage. Although macrophages can generate antimicrobial activity, neutrophils have been shown to have a key role in host defense, presumably by their preformed granules containing antimicrobial agents. Yet the mechanism by which neutrophils can mediate antimicrobial activity against intracellular pathogens such as Mycobacterium tuberculosis has been a long-standing enigma. We demonstrate that apoptotic neutrophils and purified granules inhibit the growth of extracellular mycobacteria. Phagocytosis of apoptotic neutrophils by macrophages results in decreased viability of intracellular M. tuberculosis. Concomitant with uptake of apoptotic neutrophils, granule contents traffic to early endosomes, and colocalize with mycobacteria. Uptake of purified granules alone decreased growth of intracellular mycobacteria. Therefore, the transfer of antimicrobial peptides from neutrophils to macrophages provides a cooperative defense strategy between innate immune cells against intracellular pathogens and may complement other pathways that involve delivery of antimicrobial peptides to macrophages.
The Journal of Immunology 09/2006; 177(3):1864-71. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Langerhans cells (LC) are a unique subset of dendritic cells (DC), present in the epidermis and serving as the first line of defense against pathogens invading the skin. To investigate the role of human LCs in innate immune responses, we examined TLR expression and function of LC-like DCs derived from CD34+ progenitor cells and compared them to DCs derived from peripheral blood monocytes (monocyte-derived DC; Mo-DC). LC-like DCs and Mo-DCs expressed TLR1-10 mRNAs at comparable levels. Although many of the TLR-induced cytokine patterns were similar between the two cell types, stimulation with the TLR3 agonist poly(I:C) triggered significantly higher amounts of the IFN-inducible chemokines CXCL9 (monokine induced by IFN-gamma) and CXCL11 (IFN-gamma-inducible T cell alpha chemoattractant) in LC-like DCs as compared with Mo-DCs. Supernatants from TLR3-activated LC-like DCs reduced intracellular replication of vesicular stomatitis virus in a type I IFN-dependent manner. Finally, CXCL9 colocalized with LCs in skin biopsy specimens from viral infections. Together, our data suggest that LCs exhibit a direct antiviral activity that is dependent on type I IFN as part of the innate immune system.
The Journal of Immunology 08/2006; 177(1):298-305. · 5.79 Impact Factor
-
Philip T Liu,
Steffen Stenger,
Huiying Li,
Linda Wenzel,
Belinda H Tan,
Stephan R Krutzik, Maria Teresa Ochoa,
Jürgen Schauber,
Kent Wu,
Christoph Meinken, [......],
Robert Bals,
Andreas Steinmeyer,
Ulrich Zügel,
Richard L Gallo,
David Eisenberg,
Martin Hewison,
Bruce W Hollis,
John S Adams,
Barry R Bloom,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.
Science 04/2006; 311(5768):1770-3. · 31.20 Impact Factor
-
Stephan R Krutzik,
Belinda Tan,
Huiying Li, Maria Teresa Ochoa,
Philip T Liu,
Sarah E Sharfstein,
Thomas G Graeber,
Peter A Sieling,
Yong-Jun Liu,
Thomas H Rea,
Barry R Bloom,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN- dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15 receptor. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor, promoted T cell activation and secreted proinflammatory cytokines. Whereas DC-SIGN+ macrophages were detected in lesions and after TLR activation in all leprosy patients, CD1b+ dendritic cells were not detected in lesions or after TLR activation of peripheral monocytes in individuals with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by T helper type 1 (TH1) responses. In tuberculoid lepromatous lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells seems to crucially influence effective host defenses in human infectious disease.
Nature Medicine 07/2005; 11(6):653-60. · 22.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Proliferating trichilemmal tumor is an uncommon tumor of the follicular isthmus of the hair follicle. It usually presents as a solitary nodule on the scalp of older white women. Although these lesions typically behave in a benign fashion, recurrences and metastasis after local excision have been reported. Mohs' micrographic surgery has been effectively used to treat adnexal neoplasms.
To report a case of a proliferating trichilemmal tumor in a young black man, which was excised using Mohs' micrographic surgery.
Case report and review of the literature.
Mohs' micrographic surgery demonstrated an irregular extension of the tumor beyond a 1 cm surgical margin.
Proliferating trichilemmal tumors should be considered in the differential diagnosis of cutaneous neoplasms on the scalp in persons of any age (with the possible exception of infants and children), sex, or race. Mohs' micrographic surgery may be considered an optimal treatment option for proliferating trichilemmal tumors because these lesions may have an infiltrative component that may not be clinically apparent.
Dermatologic Surgery 04/2005; 31(3):359-63. · 1.80 Impact Factor
-
Robert E Hunger,
Peter A Sieling, Maria Teresa Ochoa,
Makoto Sugaya,
Anne E Burdick,
Thomas H Rea,
Patrick J Brennan,
John T Belisle,
Andrew Blauvelt,
Steven A Porcelli,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: Langerhans cells (LCs) constitute a subset of DCs that initiate immune responses in skin. Using leprosy as a model, we investigated whether expression of CD1a and langerin, an LC-specific C-type lectin, imparts a specific functional role to LCs. LC-like DCs and freshly isolated epidermal LCs presented nonpeptide antigens of Mycobacterium leprae to T cell clones derived from a leprosy patient in a CD1a-restricted and langerin-dependent manner. LC-like DCs were more efficient at CD1a-restricted antigen presentation than monocyte-derived DCs. LCs in leprosy lesions coexpress CD1a and langerin, placing LCs in position to efficiently present a subset of antigens to T cells as part of the host response to human infectious disease.
Journal of Clinical Investigation 04/2004; 113(5):701-8. · 15.39 Impact Factor
-
Joshua R Bleharski,
Huiying Li,
Christoph Meinken,
Thomas G Graeber, Maria-Teresa Ochoa,
Masahiro Yamamura,
Anne Burdick,
Euzenir N Sarno,
Manfred Wagner,
Martin Röllinghoff,
Thomas H Rea,
Marco Colonna,
Steffen Stenger,
Barry R Bloom,
David Eisenberg,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 toward interleukin-10 and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens.
Science 10/2003; 301(5639):1527-30. · 31.20 Impact Factor
-
Stephan R Krutzik, Maria Teresa Ochoa,
Peter A Sieling,
Satoshi Uematsu,
Yolanda W Ng,
Annaliza Legaspi,
Philip T Liu,
Stewart T Cole,
Paul J Godowski,
Yumi Maeda,
Euzenir N Sarno,
Michael V Norgard,
Patrick J Brennan,
Shizuo Akira,
Thomas H Rea,
Robert L Modlin
[show abstract]
[hide abstract]
ABSTRACT: The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.
Nature Medicine 06/2003; 9(5):525-32. · 22.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To determine how distinct receptors of the immune system can contribute to innate immunity, we investigated the pattern of Toll-like receptor 1 (TLR1) and TLR2 expression in human lymphoid tissue. We found that TLR1 and TLR2 were co-expressed on cells of the innate immune system, including macrophages and dendritic cells. In addition, TLR1 and TLR2 were expressed in mucosa-associated lymphoid tissue on tonsillar crypt epithelium. Of the lymphoid tissue examined, spleen expressed the highest levels of TLR2. Although TLR1- and TLR2-positive cells were in close proximity to T lymphocytes in vivo, lymphocytes themselves were devoid of TLR1 and TLR2 expression. The co-expression of TLR1 and TLR2 on myeloid cells in lymphoid tissue provides the host with the ability to respond to a variety of microbial ligands at sites conducive to the generation of an immune response.
Immunology 02/2003; 108(1):10-5. · 3.32 Impact Factor
