How do vaccines interact with human cells?

In a recently published study, scientists have identified various transcriptional programs induced in human antigen presenting cells (APCs) by various vaccines. The article published in October issue of Nature Communications sheds new light on the mechanisms of vaccine interaction with human dendritic cells (DCs), a primary APC involved in vaccination response.

Previous studies have shown that vaccination mostly depend on dendritic cells. DCs are highly efficient in presentation of antigen. In response to a pathogen, DCs transcribe various set of genes that then interact with each other. Although, many sub-populations of DCs have been identified in human blood, skin and other tissues, the role of these populations in eliciting specific immune response to different vaccines is not entirely known. Furthermore, it is not much known about the various transcriptional programs initiated in response to different vaccines.

Romain Banchereau and colleagues from Baylor Institute for Immunology Research, Dallas and Jackson Laboratory for Genomic Medicine, Farmington used a unique multi-step approach to understand how human DCs respond to vaccine challenge in vitro. They studied transcriptional changes in DCs that were first generated by culturing monocytes (a precursor to DC) with different cytokines and then exposing them to a number of pathogens. The researchers observed a broad spectrum of unique and common transcriptional responses to pathogens over time. To further understand the biological significance of these transcriptional responses, the scientists generated a framework that groups transcripts into modules based on their co-expression across pathogens, time points, and DCs. They found that modules represented alteration of many biological pathways including interferon response, inflammation, antigen processing and presentation, DC maturation and T cell activation.

The investigators then applied the same approach to study transcriptional responses of various APCs to 13 commercially available vaccines in vitro and observed that response to different vaccine was mediated through unique APC subsets. In a further effort to understand the differences in immune pathways required for vaccination to those that are responsible for pathogenesis of a particular disease, the scientists applied the same framework to analyze transcriptional profile of individuals vaccinated with influenza vaccine and individuals with asymptomatic and symptomatic influenza infections. They found that vaccinated individuals showed similar transcriptional profiles to asymptomatic individuals and both showed a mild signature. In contrast, symptomatic individuals showed strong response. The researchers acknowledge that this approach can help in identifying which pathways are require for vaccination and which for establishing infection and this distinction between two pathways can help in development of safer and more effective vaccines in future.

Overall, this study provides a good understanding of transcriptional response of DCs to current vaccines and will certainly add in development of next generation vaccines, in which specific sub-populations of APCs can be targeted for a more effective response to a particular pathogen.

LL37 identified as an auto antigen in Psoriasis

According a new study published in nature communications, anti-microbial peptide (AMP) LL37 acts as an auto antigen in psoriasis. The study shows that LL37 was recognized as an antigen by circulating T cells in 46% of psoriatic patients. This recognition was shown by proliferation of T cells and production of interferon gamma in response to LL37. None of the controls showed such response.

Roberto Lande and colleagues from Italy and Switzerland published their findings in December issue of Nature communications. They performed their research using blood from psoriasis patients.

Psoriasis is a common condition of skin characterized by development of red scaly plaques on skin. Although it is sometimes considered an autoimmune disease, the nature of the auto antigen that leads to development of auto reactive T cells is not known. LL37 is an AMP that has been shown to be overexpressed in psoriatic skin and play important roles in pathogenesis of psoriasis. It forms complexes with extracellular self-nucleic acid. These complexes then activate plasmatoid and myeloid DCs which in turn leads to activation of T helper cells. This process then starts an inflammatory cascade. However, it was not known if LL37 can directly serve as an auto-antigen and stimulate T cells.

In this study, the authors established that psoriatic T cells were specifically responding to LL37 by showing that T cells respond only to LL37 when stimulated with a variety of other AMPs. The authors also looked at correlation of response to LL37 and disease status and found that up to 75% of psoriatic patients with moderate to severe plaque psoriasis and with a Psoriasis Activity Severity Index (PASI) score of more than 10 responded to LL37. The LL37 specific T cells in psoriasis patients showed production of pathogenic cytokines including IL17 as well as showed direct chemo tactic activity for inflammatory cells and cytotoxic ability. The study also showed that these T cells possess the ability to migrate into psoriatic skin lesions. This was further validated by finding of LL37 specific cell from skin biopsy of a psoriatic patient who earlier showed positive response of blood T cells to LL37.

In conclusion, this study shows that LL37 is an auto antigen in psoriasis and could be an appealing target to treat psoriasis.