Inbal Braunstein

CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms

ABSTRACT CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.

B and T Lymphocyte Attenuator-Mediated Signal Transduction Provides a Potent Inhibitory Signal to Primary Human CD4 T Cells That Can Be Initiated by Multiple Phosphotyrosine Motifs

The B and T lymphocyte attenuator (BTLA) is a recently identified member of the CD28 family of cell receptors. Initial reports demonstrated that mice deficient in BTLA expression were more susceptible to experimental autoimmune encephalomyelitis, indicating that BTLA was likely to function as a negative regulator of T cell activation. However, cross-linking of BTLA only resulted in a 2-fold reduction of IL-2 production, questioning the potency with which BTLA engagement blocks T cell activation. We established a model in which BTLA signaling could be studied in primary human CD4 T cells. We observed that cross-linking of a chimeric receptor consisting of the murine CD28 extracellular domain and human BTLA cytoplasmic tail potently inhibits IL-2 production and completely suppresses T cell expansion. Mutation of any BTLA tyrosine motifs had no effect on the ability of BTLA to block T cell activation. Only mutation of all four tyrosines rendered the BTLA cytoplasmic tail nonfunctional. We performed structure-function studies to determine which factors recruited to the BTLA cytoplasmic tail correlated with BTLA function. Using pervanadate as a means to phosphorylate the BTLA cytoplasmic tail, we observed both Src homology protein (SHP)-1 and SHP-2 recruitment. However, upon receptor engagement, we observed only SHP-1 recruitment, and mutations that abrogated SHP-1 recruitment did not impair BTLA function. These studies question whether SHP-1 or SHP-2 have any role in BTLA function and caution against the use of pervanadate as means to initiate signal transduction cascades in primary cells.

The interferon‐regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score

Background  There is increased expression of type I interferon (IFN)‐regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN‐regulated gene expression pointing towards a possible underlying genetic defect.Background There is increased expression of type I interferon (IFN)-regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN-regulated gene expression pointing towards a possible underlying genetic defect.

Treatment of dermatologic connective tissue disease and autoimmune blistering disorders in pregnancy

Autoimmune skin disease occurs in pregnancy, and treatment is often required to control both maternal disease and fetal outcomes. Here we present the available safety data in pregnancy and lactation for medications used to treat autoimmune skin diseases, including cutaneous lupus erythematosus, dermatomyositis, morphea and systemic sclerosis, pemphigus vulgaris, pemphigus foliaceus, and pemphigoid gestationis. A PubMed search of the English‐language literature using keywords, “pregnancy” “rheumatic disease,” and “connective tissue disease” was performed. Relevant articles found in the search and references were included. Reasonable evidence supports the careful and cautious use of topical steroids, topical calcineurin inhibitors, systemic corticosteroids, hydroxychloroquine, and azathioprine in pregnancy. Case reports or clinical experience suggest intravenous immunoglobulin, dapsone, phototherapy, rituximab, and plasmapheresis may be safe. Several treatment options exist for autoimmune skin disease in pregnancy and lactation, and should be considered when treating these patients.

Eltrombopag-Associated Hyperpigmentation

trauma. In type 2, blue-gray pigmentation occurs within previously normal-appearing skin, especially in the lower legs and forearms. Type 3 is characterized by the presence of diffuse brownish discoloration of sun-exposed areas. Histopathologically, types 1 and 2 demonstrate pigment granules in the dermis, concentrated around vasculature within macrophages, and, in type 2, around myoepithelial cells as well. Perls staining is positive in type 1. In type 2, both Perls and MassonFontana stainings are positive. In type 3, there is increased melanin in basal keratinocytes with subjacent dermal melanophages without the presence of iron. Only MassonFontana staining is positive in this type.4 Ultrastructural observations have confirmed that the clinical coloration is a result of a minocycline derivative chelated with iron that is stored within the lysosomes of macrophages. To our knowledge, there are no reports of cutaneous pigmentation due to rifampicin. Our patient’s symptoms and the histologic findings were similar to those described for minocycline pigmentation type 2 and previous cases associated with levofloxacin and pefloxacin. The course of the pigmentation is unknown, but it tends to fade if levofloxacin treatment is discontinued. Months or years are necessary to achieve resolution, although in some cases the pigmentation can be permanent. Treatment with Qswitched laser has been reported with successful results.5

Update on management of connective tissue panniculitides.

In connective tissue diseases, panniculitis can be the sole manifestation or can occur along with the underlying disease process. The best described forms of connective tissue panniculitis are lupus erythematosus panniculitis and lupus profundus, panniculitis associated with dermatomyositis, and morphea‐ and scleroderma‐associated panniculitis. These processes cause significant morbidity, such as deep atrophic scars, cosmetic disfigurement, and psychiatric sequelae. Because the inflammation is located in the subcutaneous adipose layer, topical therapies may not penetrate enough to be effective, and systemic agents are required. Despite the large number of reported cases and therapies, recommendations for treatment are based largely on case series and expert opinion due to a lack of controlled therapeutic trials. All treatments are off‐label in the United States. The lack of validated clinical outcome measures makes systematic and controlled studies difficult. Nonetheless, further investigation into the most effective therapies for these conditions is needed.

The IFN-regulated gene signature is elevated in SCLE and DLE and correlates with CLASI score

Background  There is increased expression of type I interferon (IFN)‐regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN‐regulated gene expression pointing towards a possible underlying genetic defect.Background There is increased expression of type I interferon (IFN)-regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN-regulated gene expression pointing towards a possible underlying genetic defect.

Childhood ALL and second neoplasms

Second malignancies are a significant concern for survivors of childhood acute lymphoblastic leukemia (ALL), in particular patients who have been treated with cranial irradiation. Brain tumors, most commonly meningiomas, are among the most common second neoplasms discovered in these patients. Breast cancer can occur in association with meningioma, but is not thought to be a consequence of treatment for childhood ALL. We describe the molecular genetics and therapy of childhood ALL, the molecular genetics of meningioma, as well as the possible association between meningioma and breast cancer.

The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score: IFN-regulated gene signature in CLE

Background  There is increased expression of type I interferon (IFN)‐regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN‐regulated gene expression pointing towards a possible underlying genetic defect.Background There is increased expression of type I interferon (IFN)-regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN-regulated gene expression pointing towards a possible underlying genetic defect.