Publication: “Immunomodulatory drugs have divergent effects on humoral and cellular immune responses to SARS-CoV-2 vaccination in people living with rheumatoid arthritis”

Jenna Benoit (PhD candidate) has published her first, first author paper characterizing how immune responses to vaccination differ in people living with rheumatoid arthritis. We found some interesting new drug-immune interactions.

See the full paper here.

See thread here:

or below….

New paper alert! and team studied COVID-19 vaccinations in people living with rheumatoid arthritis who are on immunosuppressive drugs and found some interesting, and to our knowledge, unknown effects of specific drugs 1/n

Almost all studies of vaccine immunogenicity (i.e., how strong an immune response is to a vaccine) focus on antibody responses. Measuring the amount of antibodies produced is cheap and (relatively) easy; however, in the Omicron-era these are less predictive of protection than you might think 2/n

When investigating anti-receptor binding domain (RBD) antibodies and team found that -unsurprisingly- people living with RA and men had lower antibody responses (men have lower antibody responses to vaccination in general), and people with COVID had higher responses (i.e., that hybrid immunity you’ve heard so much about) 3/n

What caused these lower antibody responses? DMARDs (disease modifying anti-rheumatic drugs),and anti-TNF were not associated with lower antibody levels, the effect of steroids was not significant, but costimulation inhibitors reduced antibody levels 4/n

Important caveat: The effect of co-stimulation inhibitors was about the same as being a biologic male, so whether this reduction is associated with increased risk of infection or not is not something we can comment on 5/n.

We didn’t see an effect of drugs on neutralizing antibodies (i.e., antibodies that bind the virus really well and prevent it from entering us), but we did not have enough people on some of the drugs to really investigate this 6/n.

My favourite part: CD4+ and CD8+ T cell responses to vaccination are much, much harder to measure (each dot on the graph costs about $350 and 3+ hrs of time – hence the ‘team’ I keep mentioning) but we know that they are important for preventing infection.7/n

We found that people living with RA had lower CD4+ T cell responses (= ‘helper’ cells that support many aspects of the immune response to infection & vaccination), those who had had COVID were higher – more of that hybrid immunity you’ve heard about. 8/n

BUT even though we had a small number of people on JAK inhibitors, those who were on them had markedly lower CD4+ responses. The effect of co-stimulation inhibitors was not as apparent – but again low numbers of participants so hard to say. 9/n

Speculative side note: We use influenza vaccine as a control. Everyone has had exposure as kids so this measures a memory response made prior to having been vaccinated. Co-stim inhibitors don’t affect influenza but JAK inhibitors do – therefore no defect in pre-drug immune responses? 10/n

CD8+ T cell responses (‘killers’ of virus infected cells), were higher in men (previously known), and didn’t seem to be lower in most drugs, except maybe steroids. 11/n

Caveats: Our study was small and due to the fact we were measuring 1,2,3 doses, we were recruiting fast and furious and didn’t capture as many people on some of the drugs as we would have liked,so all results need to be replicated. 12/n

Clinical relevance: Some of these drugs are associated with increased risk of severe disease (see text for references) and by learning which aspects of the immune response they affect, we learn which aspects of the immune response are required for a successful vaccine. 13/n

Deepest appreciation for our research participants, the Canadian Arthritis Patient Alliance (see website for talks on this topic), the SUCCEED investigator team, our technical staff, fundign from the Public Health Agency of Canada, and you for reading to 14/n

Dr. Jessica Breznik talks about her research in the American Journal of Physiology-Gastrointestinal and Liver Physiology Podcast

In this podcast first author Dr. Jessica A. Breznik of McMaster University, discusses the recently published manuscript titled “Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages and increases intestinal permeability in female mice independent of tumor necrosis factor.” 

NEW & NOTEWORTHY We found that diet-induced obesity in female mice has tissue- and time-dependent effects on intestinal paracellular permeability as well as monocyte-derived and tissue-resident macrophage numbers, surface marker phenotype, and intracellular production of the cytokines IL-10 and TNF. These changes were not mediated by TNF.

Article Citation: Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages and increases intestinal permeability in female mice independent of tumor necrosis factorJessica A. Breznik, Jennifer Jury, Elena F. Verdú, Deborah M. Sloboda, and Dawn M. E. Bowdish

American Journal of Physiology-Gastrointestinal and Liver Physiology 2023 324:4, G305-G321

Bowdish lab research on the evolution of MARCO featured in the New York Times

Our research on the scavenger receptor MARCO was featured in an article “Air Pollution, Evolution, and the Fate of Billions of Humans” by Carl Zimmer in the New York Times. In this manuscript we collaborated with Dr. Brian Golding, an expert in evolutionary biology in order to understand the evolution of this macrophage receptor. MARCO (or macrophage receptor with collagenous structure) is expressed on macrophages where it binds bacteria and particles such as those found in dust and air pollution. We had hypothesized that because it is the receptor for two pathogens, Streptococcus pneumoniae and Mycobacterium tuberculosis, that have played a major part in driving human evolution, that we might find evidence of areas of the receptor that were undergoing rapid evolution to protect us from this pathogen.

In order to determine which regions of the protein were changing we performed a phylogenetic analysis of the sequence of MARCO from humans, our close ancestors, the Denisovians and Neanderthals, and primates. We found a few interesting things. There was one mutation, which we call F282S (282 refers to the 282nd amino acid in the protein, the F = phenylalanine and the S= serine), had changed very rapidly. All our primate, Denisovian and Neanderthal relatives had a serine residue in that position but fully 83% of the human genomes we analyzed had a phenylalanine. The fact that this mutation spread so quickly through the population means that there must have been very strong selection pressure. We cloned both variants and found that the human specific variant was indeed better at binding inert particles and bacteria. There were a few other interesting mutations we characterized (see article below) but the take home message is that some of the evolutionary adaptations we have made to deal with pathogens may have influenced our ability to handle air pollution or, since the savannah was predicted to be a dry and dusty place, the adaptations we’ve made to deal with particulates in the air may have changed our response to pathogens.

To read the full article, see below.

Human-specific mutations and positively-selected sites in MARCO confer functional changes. Novakowski KE, Yap NVL, Yin C, Sakamoto K, Heit B, Golding GB, Bowdish DME. Mol Biol Evol. 2017 Nov 20. doi: 10.1093/molbev/msx298.
PMID: 2916561

Publication: Age-associated Inflammation alters the aging trajectory.

This article is written for lay/broad audiences and describes what age-associated inflammation is and why it may be key to healthy/unhealthy aging.

White paper: “Paving The Way For Immunization Innovation” with the Lung Association Ontario

Publication: Myeloid-Derived Suppressor Cells in Aged Humans

Myeloid-Derived Suppressor Cells in Aged Humans

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells whose
immunosuppressive activities contribute to cancer and other diseases. MDSCs
appear to increase with age, and this presumably contributes to immunosuppression
and the increased incidence of certain diseases. Why MDSCs increase with
age is not entirely clear. Herein we present evidence that MDSC expansion is due
in part to age-related changes in hematopoiesis, including the acquisition of
mutations that favor myelopoiesis, which are compounded by changes in the
aging microenvironment that favor the production of MDSCs.