Cell of Origin and Biologic Correlates
Immunologic Abnormalities
Etiology
Chromosomal Studies
Cytokine Analysis by Immunohistochemical Staining
Gene Expression by Microarray Analysis
Cytokine Levels and Association with Diagnosis, Prognosis or Response to Therapy
Human Leukocyte Antigen Type and Association with Langerhans Cell Histiocytosis

Cell of Origin and Biologic Correlates

The Langerhans cell (LC) originates from bone marrow stem cells as an immature dendritic cell (DC) which can then develop into the LC under the influence of several cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF alpha), and others.[1] These immature cells are found in the skin, lymph nodes, spleen, bone marrow, and lungs. LCs differ from other histiocytes in that they are CD1a-positive and CD207 (langerin)-positive.[2] This cell characteristic along with the classic histology (see below) is used to identify LCs in lesions where they also maintain an immature dendritic cell phenotype (see below).[3] Suspected Langerhans cell histiocytosis (LCH) lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts and sometimes multinucleated giant cells. It has been proposed that the LC is the cellular pathologic culprit for LCH lesions, however, definitive evidence of this has yet to be obtained.[2]

In the brain, three types of histopathologic findings have been described in LCH:

Granulomas in meninges or choroid plexus with CD1a+ LC and predominantly CD8+ lymphocytes.

Granulomas in connective tissue spaces with CD1a+ LC and predominantly CD8+lymphocytes causing an inflammatory response and neuronal loss.

Predominantly CD8+ lymphocyte infiltration with tissue degeneration, microglial activation and gliosis.[4]

Normally, the LC is a primary presenter of antigen to naïve T lymphocytes. However, in LCH, the LC does not efficiently stimulate primary T lymphocyte responses.[5] Antibody staining for the DC markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature DCs that present antigen poorly and are proliferating at a low rate.[3,6] Transforming growth factor-beta (TGF-beta) as well as interleukin (IL)-10 are possibly responsible for preventing LC maturation in LCH.[3] The expansion of regulatory T cells in LCH patients has been reported.[6] The population of CD4+ CD25 high FoxP3high cells was reported to comprise 20% of T cells and appeared to be in contact with LC in LCH lesions. These T cells were present in higher numbers in the peripheral blood of LCH patients than in controls and returned to a normal level when patients were in remission.

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[7,8]

Studies showing clonality in LCH have been published since 1997 using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT.[9,10] Biopsies of lesions with single system or multisystem disease were found to have a proliferation of LCs from a single clone. Pulmonary LCH in adults is usually nonclonal.[11] Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone (t7;12)(q11.2;p13) from a vertebral lesion of one patient.[12] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

Three studies have used comparative genomic hybridization (CGH) to analyze bone and pulmonary LCH.[13-15] Analysis of seven bone lesions by CGH and loss of heterozygosity (LOH) has provided further evidence to suggest that chromosomal aberrations may be an intrinsic problem in LCH.[13] One study evaluated 14 cases of pulmonary LCH for LOH [14] and found LOH of 1p, 1q, 3p, 5p, 17p and 22q. Allelic loss of one or more tumor suppressor genes was identified in 19 of 24 specimens. Researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins demonstrated that significantly shortened telomeres in the LCH lesional LCs compared with LCs in inflammatory disorders such as dermatopathic lymphadenitis.[16] An Italian group demonstrated that high-risk LCH patients had DNA polymorphisms of two cytokine genes (IL-4 and interferon gamma) which were associated with high-expresser phenotypes.[17]

Several cytokines have apparent higher expression levels in LCH lesions than in normal tissue. Among the cytokines expressed at high levels are GM-CSF, interferon gamma, IL-1, sIL-2r, IL-10, and the TNF receptor family member, RANK.[6,18] Lesional T cells stain with antibodies to TNF alpha, various interleukins, CD40L, and sCD154.[18,19] Prominent expression of angiotensin-converting enzyme, TGF-beta, and IL-11 in LCH biopsies have been reported.[20] Increased expression of the chemokine receptor, CCR6, has been observed in LCH lesions and may contribute to the accumulation of LCs in skin. Increased CCR7 expression may cause the LC to home to lymphoid tissue.[21] These data are somewhat anomalous because it is expected that CCR6 would be down-regulated in the activated LCs in these lesions. However, prominent staining of CCR6 and its ligand CCL20/M1P-3alpha has been found in other studies.[22] Further evidence for the altered biology of LCs in LCH is the increased expression of the antiapoptotic protein, Bcl-2, as well as several other genes (e.g., Ki-67, TGF-beta receptors 1 and 2, MDM2, p53, p21, p16, and RB).[23]

Two papers have been published on analysis of gene expression in LCH by gene array techniques.[24,25] In the first report, a laser-capture microdissection was used to purify LCs from frozen biopsy specimens or normal LCs from the skin.[24] The level of cytokine and growth factor gene expression in the control LCs versus those from patient biopsies showed a striking similarity in expression of RNA of the TNF family of genes and several interleukins. Only macrophage colony-stimulating factor (M-CSF), TGF-beta receptor and IL-1 alpha transcripts were expressed at higher levels in the LCs from LCH patients. In the second report, a very different approach was used, generating LCs from CD34 stem cells in vitro followed by a serial analysis of gene expression library to identify highly expressed genes in these LCs.[25] Several of the highly expressed genes were then chosen to test for RNA levels from whole LCH biopsy specimens. High expression of FSCN1, GSN MMP12, CCL22, CD1a and CD207 was commonly observed.

Several groups have measured cytokines or other markers of immune activation in the plasma or serum of patients with LCH to determine whether these levels could be of diagnostic or prognostic importance or whether the levels could be helpful for evaluating response to therapy. One group reported consistently higher levels of IL-2 receptor in LCH biopsy specimens,[26] however, they found no increased expression of IL-1beta, TNF-alpha, and IL-2, which were all within normal limits. Another group used a similar assay technique and identified increased levels of the IL-1 receptor agonist and TNF-alpha in plasma from LCH patients.[27] Vascular endothelial growth factor has also been identified by immunohistochemistry in five of five patients with multisystem LCH and two of five patients with single system LCH.[28] A third group found markedly elevated levels of FLT3-ligand and M-CSF in the serum of LCH patients with good correlation to the extent of disease as well as response to treatment and increased circulating immature myeloid dendritic cells.[29] It should be noted that this latter finding was not confirmed by a later study; however, there was a trend toward higher myeloid DC levels in patients.[6] Elevated levels of another regulator of the immune system and bone metabolism, osteoprotegerin (OPG), are present in the plasma of patients with active LCH.[30,31] OPG levels reported in this study were highest in patients with multisystem disease and decreased with response to therapy, similar to the findings with FLT-3 ligand and M-CSF.

Specific associations of LCH with distinct human lymphocyte antigen (HLA) types and extent of disease have been published. In a study of 84 Nordic patients, those with only skin or bone involvement more frequently had HLA-DRB1*03 type than those with multisystem disease.[32] In 29 patients and 37 family members in the United States, the Cw7 and DR4 types were significantly more prevalent in Caucasians with single bone lesions.[33]

References

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