Archive for the ‘Inflammation’ Category

Re-Cap of LDA/Columbia Lyme Conference

https://www.lymedisease.org/lda-columbia-lyme-conference/

LYME SCI: My re-cap of recent LDA/Columbia Lyme conference

On October 2, I attended the 21st annual scientific conference put on by the Lyme Disease Association and Columbia University’s Vagelos College of Physicians & Surgeons. The virtual event was entitled Lyme & Other Tick-Borne Diseases: Research for a Cure. 

Pat Smith, President of the Lyme Disease Association, welcomed the audience and reviewed the huge body of research the LDA has funded. A recent highlight: a paper showing that changes in the eye may serve as a biomarker for Lyme disease.

She also discussed how the CDC’s criteria for listing states as low-incidence leads to underreporting of Lyme disease. (This topic was also featured in the Summer 2021 issue of The Lyme Times.)

I especially enjoyed Pat’s introduction of Dr. Brian Fallon, of Columbia University, which included pictures and stories of their many collaborations since 1995.

The conference was divided into four sessions and was moderated by Dr. Fallon and Monica Embers, PhD, of Tulane University.

Session 1

The first speaker was John Aucott, MD, of Johns Hopkins University. He spoke on Long Haulers: Lessons from Lyme Disease, ME/CFS, and COVID-19.

Summary: The COVID-19 pandemic has drawn attention to the varied outcomes that may follow acute infectious diseases. COVID long haulers present another example of a patient group that fails to recover their normal health after the initial phase of infection has passed. Long haulers in COVID 19 and Lyme disease share many clinical features including extreme fatigue, cognitive difficulties and chronic pain. The current COVID-19 pandemic may present insights and research discoveries that help understand the underlying mechanisms involved in such persisting symptoms. Understanding the cause of these chronic symptoms is the first step to future treatments and recovery.

Dr. Aucott is currently collaborating with several of the following researchers to investigate the proposed mechanisms of chronic Lyme including: persistent infection, immune dysregulation due to by-products of past infection, auto-inflammation, auto-immunity, and neural network alteration. (I will be writing more about these mechanisms in my next article.)

Next up was Dr. Fallon’s talk: Depression, Suicidal Behaviors, and Lyme: Results from a Nationwide Study in Denmark.

Summary: This presentation reviewed the results of  Dr. Fallon’s recent U.S.- Denmark collaboration to determine whether in fact mental disorders and suicidal behaviors are increased after the diagnosis of Lyme disease. Although cases reports, small series, and office-based practice chart reviews have been published suggesting an association, these studies all had methodological limitations which left these questions unanswered.

Using a nationwide sample of people living in Denmark between 1994 and 2016 (n=6,945,837) and data from the Danish registries of hospital-based diagnoses, they investigated whether the rates of mental disorders, affective disorders, suicide attempts, and suicide were each higher after a hospital diagnosis of Lyme borreliosis compared to the rest of the Danish population without a registered diagnosis of Lyme borreliosis. They examined whether temporal proximity to the diagnosis and number of episodes increased the rates of these adverse mental health outcomes.

The researchers found that individuals with Lyme disease had a 28% higher rate of mental disorders, 42% higher rate of mood disorders and 75% higher rate of death by suicide when compared to the non-Lyme controls.

The third speaker of the morning was Ed Breitschwerdt, DVM, of North Carolina State University. He spoke on: Bartonella Bacteremia and Neuropsychiatric Illnesses.

Summary: In the past two decades, over 40 Bartonella species have been discovered, many of which have been implicated in association with a spectrum of disease in animals and human patients. The extent to which, or the mechanisms by which Bartonella infection contributes to neuropsychiatric illnesses has not been systematically studied. However, microbiological detection of the DNA of several species of Bartonella in blood supports a potential role for these bacteria in neuropsychiatric diseases such as Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) and schizophrenia.

In 2021, Dr. Breitschwerdt and his lab published the initial results of a pilot study showing that out of 17 patients with schizophrenia, 12 tested positive for Bartonella in their blood. They now have funding to proceed with a larger study that will include diagnosis and treatment for Bartonella.

Q and A

At the end of Session 1, Dr. Embers moderated the questions and answers  session. I found it enlightening to have these high-level researchers and clinicians answering questions from the audience, including other scientists.

I asked a question about co-infections: “It appears both Lyme and Bartonella patients are prone to psychiatric illness. Has anyone looked at or compared the number of patients who have both? Do we know if these [Fallon study] Lyme patients have Bartonella, or do we know how many of the Bartonella patients [Breitschwerdt study] have Lyme?”

Dr. Breitschwerdt said it is important to track this and that the work coming out of his lab as well as Embers’ work is helping to elucidate. Embers added:

Borrelia may be comparable to AIDS, in its ability to suppress the immune system and these co-infections definitely warrant further study.”

Session 2

The first speaker of session two was Brandon L. Jutrus, PhD, of Virginia Tech. The title of his talk: Not just another brick in the wall.

Summary: The unusual peptidoglycan of Borrelia burgdorferi. The peptidoglycan sacculus is a mesh-like bag that protects bacterial cells from bursting. Virtually all bacteria have similar peptidoglycan structure. Borrelia burgdorferi—the Lyme disease agent— produces peptidoglycan with extremely unusual chemical features. Further, during growth, peptidoglycan is shed and is capable of causing arthritis. He discussed how the Jutras lab is exploiting the unusual properties of B. burgdorferi peptidoglycan to understand and diagnose Lyme disease.

Dr. Jutrus presented some unpublished data that may lead to an early diagnostic test and targeted treatment for Lyme.

The next speaker was Catherine A. Brissette, PhD, of the University of North Dakota School of Medicine and Health Sciences. The title of her talk: Borrelia colonization of the dura mater induces inflammation in the CNS.

Summary: “Lyme disease, which is caused by infection with Borrelia burgdorferi, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems including the central nervous system (CNS). Laboratory mice have been used to define the kinetics of B. burgdorferi infection and host immune responses in other tissues, but similar studies are lacking for the CNS of these animals. Previously, we reported the ability of B. burgdorferi to colonize the dura mater of mice during late disseminated infection. We now show acute and persistent extravascular B. burgdorferi colonization of the dura mater after both needle inoculation and tick transmission, accompanied by increases in expression of inflammatory cytokines. These increases in inflammatory gene expression are similar to what is observed with B. burgdorferi stimulation of human astrocytes, microglia, brain endothelial cells, and choroid plexus epithelial cells in vitro. In addition, we observe a robust interferon response in the dura mater. Dura colonization is associated with perivascular leukocyte infiltration and meningitis, demonstrating for the first time that B. burgdorferi-infected mice can develop meningitis. We also observe an increase in interferon-stimulated genes in both the cortex and hippocampus of infected mice, despite a lack of detectable bacteria in the brain parenchyma. Combined with the increases in inflammatory gene expression and down-regulation of genes involved in maintenance of blood-brain and blood-CSF barriers in both mice and human cell culture models, these results could provide insights into the mechanism of B. burgdorferi dissemination into the CNS and the damage associated with this pathogen.”

The last speaker of Session 2 was Adrian Baranchuk, MD, FACC, FRCPC, FCCS, FSIAC, of Queen’s University in Ontario, Canada. The title of his talk: All you need to know about Lyme carditis…and more.

Summary: Lyme disease (LD) is a tick-borne bacterial infection caused by Borrelia burgdorferi. It is the most reported vector-born disease in North America, and its incidence has risen dramatically in recent years. In up to 10% of cases, bacterial dissemination of LD may lead to cardiac tissue inflammation and early disseminated Lyme carditis. The most common clinical presentation of Lyme carditis is high-degree atrioventricular block (AVB) which can progress rapidly over minutes, hours, or days. Most AVB in Lyme carditis resolves with appropriate antibiotic treatment without the need for a permanent pacemaker.

Dr. Baranchuk, encourages medical providers to do an ECG on all patients with cardiac symptoms and to consider Lyme carditis when heart block is observed.

Another Q & A

At the end of Session 2, there was another question and answer time, moderated by Dr. Fallon. Let me just say the work coming out of the labs of Dr. Jutrus and Dr. Brissette is groundbreaking. I will definitely be writing more about what I learned from this session.

Session 3

The first speaker for session three was Dr. Monica Embers, on the topic of Combined Antimicrobial Therapy for Eradication of B. burgdorferi.

Summary: Given the potential for standard antibiotic treatment regimens for Lyme disease to fail to eradicate persisters, we aim to discover a drug combination that can eliminate B. burgdorferi infection. The goals of this project are to: (1) using a library of FDA-approved drugs, identify the optimal antimicrobial combinations that could kill B. burgdorferi in vitro; and (2) test them in animal models of Lyme disease for cure of infection. The most effective combinations of drugs that kill the bacteria have been identified with in vitro studies. These were then evaluated in B. burgdorferi-infected mice, using long-term infection to allow for regrowth of persisters. Finally, the most effective regimens are being assessed in nonhuman primates. Importantly, we have refined the selection of drugs to those that can be administered orally.

Next, Kim Lewis, PhD, of Northeastern University, spoke about Developing therapies for Lyme disease.

Summary: Symptoms of Post-Treatment Lyme Disease Syndrome (PTLDS) are experienced by approximately 10% of patients after antibiotic therapy for an acute B. burgdorferi infection. The underlying causes of PTLDS symptoms have remained unclear. We reasoned that the gut microbiome may play an important role in PTLDS given the overlapping symptoms associated with a dysbiotic microbiome, including mood, cognition, and autoimmune disorders. Using sequencing data from stool of a cohort of PTLDS patients, we identified a gut microbiome signature characterized primarily by high relative abundance of Blautia species and reduction in levels of the symbiotic Bacteroides genus. These findings suggest that Lyme disease should be treated with selective antibiotics that will not harm the microbiome. We find that hygromycin A selectively kills B. burgdorferi and cures the acute disease in a mouse model without affecting the microbiome.

The last speaker for session three was Kenneth B. Liegner, MD, discussing Disulfiram in the Treatment of Lyme disease: Promise & Perils.

Summary: Some four years have elapsed since disulfiram was first knowingly applied in the treatment of persons with Lyme disease. Dr. Liegner reviewed several trial cases of patients with Lyme disease who responded positively to disulfiram. He cautioned that the drug comes with a strong warning against alcohol use/proximity, and cross-reactions to certain other medications.

Learn more about disulfiram and why is it sparking excitement in Lyme community.

Q and A

The Q&A segment at the end of session 3 was moderated by Dr. Fallon. It was really fantastic to have Dr. Liegner who has been treating Lyme patients for the past 30 years, be able to interact with these researchers who are both currently working hard to finding a cure for Lyme disease. Dr. Fallon made a point of stating the use of disulfiram is experimental and not currently approved for Lyme disease.

Session 4

Session four began with Marna Erricson, PhD, of the University of Minnesota. She spoke on Bartonella henselae Detected in Malignant Melanoma

Summary: Bartonella bacilliformis (B. bacilliformis), Bartonella henselae (B. henselae), and Bartonella quintana (B. quintana) are bacteria known to cause verruga peruana or bacillary angiomatosis, vascular endothelial growth factor (VEGF)‐dependent cutaneous lesions in humans. Given the bacteria’s association with the dermal niche and clinical suspicion of occult infection by a dermatologist, we determined if patients with melanoma had evidence of Bartonella spp. infection. Within a one‐month period, eight patients previously diagnosed with melanoma volunteered to be tested for evidence of Bartonella spp. exposure/infection. Subsequently, confocal immunohistochemistry and PCR for Bartonella spp. were used to study melanoma tissues from two patients. Blood from seven of the eight patients was either seroreactive, PCR positive, or positive by both modalities for Bartonella spp. exposure. Subsequently, Bartonella organisms that co‐localized with VEGFC immunoreactivity were visualized using multi‐immunostaining confocal microscopy of thick skin sections from two patients. Using a co‐culture model, B. henselae was observed to enter melanoma cell cytoplasm and resulted in increased vascular endothelial growth factor C (VEGFC) and interleukin 8 (IL‐8) production. Additionally, the two tissues also were found to have BRAF mutations, an oncogene expressed in up to 70% of melanomas. Findings from this small number of patients support the need for future investigations to determine the extent to which Bartonella spp. are a component of the melanoma pathobiome. Being at the frontier of understanding the role of the microbiome in cancer, we will discuss some new papers on this topic and future research plans.

The final speaker of the day was, Richard Maggi, PhD, North Carolina State University. His topic: Simultaneous detection and absolute quantification of Babesia, Bartonella and Borrelia by droplet digital PCR.

Summary: This presentation describes the development, optimization, and validation of a ddPCR assay for the simultaneous detection of Babesia, Bartonella, and Borrelia spp. DNA from several sample matrices, including clinical blood samples from animals and patients, vectors (ticks, fleas, sandflies), as well as samples from human and animal cell lines and tissues from animal models (infected with Bartonella and/or B. burgdorferi). The multiplex ddPCR assay (BBB ddPCR), developed based upon a recently published a Bartonella ddPCR assay using the QX200 system from Bio-Rad, is able to detect 31 Bartonella spp. (including 8 previously uncharacterized species), 8 Borrelia spp, and 24 Babesia spp. (including 8 previously uncharacterized species). The assay is also able to detect 2 Theilaria spp. (T. equi and T. cervi) and well as C. felis from naturally infected wildlife species. The BBB ddPCR assay, based on the QX One ddPCR system from Bio-Rad, showed to be able to perform the simultaneous detection and absolute quantification of multiple vector-borne pathogens (such as Babesia, Bartonella and Borrelia) from clinical samples.

Q & A

The Q&A at the end was moderated by Dr. Embers. The research presented by these two was highly technical, but I can say their work will provide better diagnostics that will lend to each of the previous researcher work.

LymeSci is written by Lonnie Marcum, a Licensed Physical Therapist and mother of a daughter with Lyme. She serves on a subcommittee of the federal Tick-Borne Disease Working Group. Follow her on Twitter: @LonnieRhea  Email her at: lmarcum@lymedisease.org.

Alternative Treatments for Lyme Disease Symptoms Brings New Hope

http://  Approx. 3 Min

Alternative Treatments for Lyme Disease Symptoms Brings New Hope

Sept. 21, 2021

News Center Maine

The multi-step, laser therapy treatment targets the biofilm that surrounds the bacteria that causes Lyme disease.

Correction: 

The news segment falsely states that only 25% go on to suffer from lingering symptoms.  This article, reveals that they achieve that low number by only counting patients who are diagnosed and treated early.  There is a much larger patient group (30-40%) that due to being undiagnosed or misdiagnosed, that is diagnosed and treated much later (months to years).  When you simply add the two groups you discover that 60% of patients go on to suffer sometimes life-long symptoms. This is a big deal and needs to be corrected, but the CDC is constantly manipulating criteria and numbers for a pre-determined outcome that fits their accepted narrative.  And the accepted narrative for Lyme/MSIDS has always been and continues to be that it is hard to catch and easy to treat.

Some reasons these numbers matter:

  • using the faulty 25% downplays a real problem that is much larger in scope
  • research projects are typically done on issues involving the most people, so those suffering from persistent symptoms continue to be ignored in research
  • in order to qualify for entrance into research studies:
    • patients must test positive on the abysmally inaccurate 2-tiered CDC serology test that misses more than 70% of all cases and here 86%
    • patients must have the EM rash which is often missed or mischaracterized by physicians, can look different on patients, and which is often missing altogether in many
    • have a positive diagnosis which in a maddening never-ending loop is based on faulty testing 
Chronic Lyme patients are continually kicked to the curb due to faulty parameters that are regurgitated like a 3 year old reciting the alphabet with no understanding of it. 

I’ve posted on lasers before and we had a practitioner speak about them at support group. 

Please see:

Of course there are numerous types of lasers and the one presented in the news story is different then the class IV laser which I have had treatments with. Unlike the one presented in the news story, the class IV laser is very hot and must be moved continually or it would burn you.  The best way to describe the feeling is that it feels like your muscles have turned to butter.  I would compare it to a massage without the pain. It’s relaxing and quite effective against pain.  It does come with a price – when I had it done it was about $100 for about a 40 min. treatment.  I do highly recommend Raymond as he is not only trained with the laser but is a naturopath with great ideas. 

Until testing can distinguish between whether we are in active infectious state or just suffering from lingering symptoms that antimicrobials will not solve we are Guinea Pigs trying this and that for relief.

I’ve found the following things all help with pain:

Lastly, for me I had chronic headaches that felt like a horse kicked me in the head.  Seriously, I never knew that people could survive such unbelievable pain. Mostly at the brain stem (occipital area), the inflammation was so severe I eventually had a MRI to rule out Chiari.  I found that daily minocycline (a drug known to cross the blood/brain barrier) truly was one of the most effective things I used (I would put tinidazole in this category as well).  I do feel it’s important to layer treatment to mitigate any antibiotic resistance, so we always took 2-3 other antimicrobials simultaneously as well as pulsed diflucan to mitigate any yeast issues.

 

 

LDN Webinar

https://www.belmarpharmasolutions.com/resources/clinician-resources/clinician-library/the-ldn-book-volume-two/

**Please note this webinar occurred last year; however, they are making it available to all now.  Just go to the link, fill out info. and you will be directed to the Webinar that already took place.**

The LDN Book: Volume Two

October 12, 2020

By: Belmar Pharmacy

Belmar Pharmacy is presenting the launch of Author and Low Dose Naltrexone (LDN) Advocate, Linda Elsegood’s latest book, The LDN Book Volume 2.

Dr. Angela DeRosa, Belmar Pharma Solutions Medical Director and Tracy Crawford, Director of Customer Experience, speak with authors Linda Elsegood, Darin Ingels ND, FAAM, Olga Cortez MD, and Leonard Weinstock MD about their LDN expertise and their contributions to the book.

Also hear from, Samantha Lebsock, PharmD at Belmar Pharmacy – she will share her extensive knowledge of LDN from a compounding pharmacist perspective. 

This webinar is engaging for both practitioners and patients interested in learning more about LDN and how to get their hands on The LDN Book Volume 2 and all it has to offer.

Conversations contain some of the reasons practitioners prescribe LDN, including:

  • Autoimmune
  • Women’s Health
  • Lyme Disease
  • Thyroid
  • Chronic Skin Conditions
  • Gut Health

This webinar is intended for patients and prescribers. If you would like to watch the webinar, please fill out in the top link. You will be re-directed to the recording after the successful completion of the form.

For more on LDN:

Vaccine-Induced Thrombocytopenia With Severe Headache – Why Lyme/MSIDS Patients Should Care

https://www.nejm.org/doi/full/10.1056/NEJMc2112974?

Vaccine-Induced Thrombocytopenia with Severe Headache

To the Editor:

Vaccine-induced immune thrombotic thrombocytopenia (VITT), a serious adverse event after vaccination with ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & Johnson–Janssen), is caused by platelet factor 4 (PF4)–dependent, platelet-activating antibodies.1-3 High-dose immune globulins and anticoagulation are the main treatments.4,5 In this report, we present evidence that vaccine-induced thrombocytopenia (VIT) without associated cerebral venous sinus thrombosis (CVST) or other thromboses and with severe headache as the heraldic symptom may precede VITT (“pre-VITT syndrome”).

Eleven patients presented with severe headache in the absence of CVST 5 to 18 days after ChAdOx1 nCoV-19 vaccination.

  • All the patients had thrombocytopenia (low platelets in the blood which can cause hemorrhaging)
  • high d-dimer levels (a test to detect blood clots – a high level indicates clot formation and breakdown in the body)
  • high levels of anti–PF4–heparin IgG antibodies
  • during follow-up, intracranial hemorrhage occurred in three patients (Patients 1, 2, and 3), with radiologic evidence of new CVST in Patients 2 and 3 (Figure 1, and Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).
  • Only two patients (Patients 2 and 4) were initially admitted with conditions that met the criteria for VITT; both patients had pulmonary embolism, and additional splanchnic vein thrombosis was present in Patient 2.

In Patient 2, anticoagulation treatment had been initiated several days earlier for pulmonary embolism (without diagnosis of VITT) but was stopped after the onset of headache, shortly before CVST developed.

  • In two patients (Patients 1 and 3), peripheral thromboses were eventually identified during follow-up.

Thrombotic complications did not develop in seven of the patients (Patients 5 through 11); all but one of these patients received high-dose immune globulin, glucocorticoids, or therapeutic-dose anticoagulation within 5 days after headache onset. In contrast, in all four patients with subsequent thrombosis (Patients 1 through 4), therapeutic-dose anticoagulation either was not started until 6 to 9 days after headache onset or was stopped prematurely before the development of CVST.

Although the combination of thrombocytopenia and severe headache due to CVST has been recognized as the typical presentation of VITT,1,2 the experience with these 11 patients suggests that VIT with severe headache, elevated d-dimer levels, and strongly positive results on anti–PF4–heparin IgG enzyme-linked immunosorbent assay may precede VITT.

Our findings have immediate implications for clinical practice: in this pre-VITT syndrome, severe headache may not develop as a symptom secondary to CVST but instead may precede CVST by several days, potentially in association with microthrombosis in smaller cortical veins.

Consequently, patients who present with severe headache 5 to 20 days after adenovirus vector vaccination against coronavirus disease 2019 should undergo immediate testing for thrombocytopenia and d-dimer levels and, if available, testing for anti–PF4–heparin IgG antibodies.

When these antibodies are present at high titers, patients are at imminent risk for CVST, and it is likely that this condition can be prevented with immediate treatment, such as with intravenous immune globulin. The decision to initiate therapeutic-dose anticoagulation is a difficult one; the risk of emerging thrombosis, including CVST, has to be balanced against the risk of intracranial hemorrhage on an individual basis (e.g., with consideration of platelet count and fibrinogen levels).

Farid Salih, M.D.
Charité-Universitätsmedizin Berlin, Berlin, Germany

Linda Schönborn, M.D.
Universitätsmedizin Greifswald, Greifswald, Germany

Siegfried Kohler, M.D., Christiana Franke, M.D., Martin Möckel, M.D., Thomas Dörner, M.D., Hans C. Bauknecht, M.D., Christian Pille, M.D., Jan A. Graw, M.D.
Charité-Universitätsmedizin Berlin, Berlin, Germany

Angelika Alonso, M.D.
University Hospital of Mannheim, Mannheim, Germany

Johann Pelz, M.D.
University Hospital of Leipzig, Leipzig, Germany

Hauke Schneider, M.D., Antonios Bayas, M.D., Monika Christ, M.D.
University Hospital of Augsburg, Augsburg, Germany

Joji B. Kuramatsu, M.D.
University Hospital of Erlangen, Erlangen, Germany

Thomas Thiele, M.D., Andreas Greinacher, M.D.
Universitätsmedizin Greifswald, Greifswald, Germany

Matthias Endres, M.D.
Charité-Universitätsmedizin Berlin, Berlin, Germany

Supported by Deutsche Forschungsgemeinschaft project number 374031971–TRR 240 (to Prof. Greinacher) and EXC-2049–390688087 NeuroCure under the German Excellence Strategy (to Prof. Endres) and by the Domagk-Programm of the Universitätsmedizin Greifswald (to Dr. Schönborn).

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on September 15, 2021, at NEJM.org.

Profs. Greinacher and Endres contributed equally to this letter.

___________________

**Comment**

Both Thrombocytopenia and severe headaches are common with Lyme/MSIDS patients.

Therapy for thrombocytopenia requires treatment or removal of the underlying infection, in addition to maintenance of platelet counts and hemostatic function.

Hopefully it’s clear that a Lyme/MSIDS patient getting a COVID shot could be diagnosed with thrombocytopenia that either already exists or worsens after the injection.  Treating the underlying infection is imperative but won’t be considered by mainstream medicine.

For more:

Go here for the latest VAERS data and the mounting list of adverse reactions and deaths.

Cellular Blueprint of MS Lesions

https://www.nih.gov/news-events/news-releases/nih-scientists-build-cellular-blueprint-multiple-sclerosis-lesions

Friday, September 10, 2021

NIH scientists build a cellular blueprint of multiple sclerosis lesions

Study lays the groundwork for potential new therapies for progressive multiple sclerosis.

Chronic lesions with inflamed rims, or “smoldering” plaques, in the brains of people with multiple sclerosis (MS) have been linked to more aggressive and disabling forms of the disease. Using brain tissue from humans, researchers at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) built a detailed cellular map of chronic MS lesions, identifying genes that play a critical role in lesion repair and revealing potential new therapeutic targets for progressive MS. The study was published in Nature.

“We identified a set of cells that appear to be driving some of the chronic inflammation seen in progressive MS,” said Daniel Reich, M.D., Ph.D., senior investigator at NINDS. “These results give us a way to test new therapies that might speed up the brain’s healing process and prevent brain damage that occurs over time.”

Chronic active lesions are characterized by a slow, expanding rim of immune cells called microglia. Microglia normally help protect the brain, but in MS and other neurodegenerative diseases, they can become overactive and secrete toxic molecules that damage nerve cells. Other cells found at the edge of the lesions, such as astrocytes and lymphocytes, may also contribute to ongoing tissue damage. Prior studies suggest that microglia are the main culprits behind lesion expansion, but the exact types of cells found near lesions and their biological mechanisms are elusive.

To better understand MS lesions, Dr. Reich and his colleagues used single-cell RNA sequencing, a powerful technique which enables researchers to catalog gene activity patterns in individual cells, to examine post-mortem brain tissue of five MS patients and three healthy controls. Samples were provided by the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands, and the NINDS Neuroimmunology Clinic.

“Single-cell RNA sequencing technology allows us to do a much deeper dive into the types of cells present in MS lesions,” said Dr. Reich.

By analyzing the gene activity profiles of over 66,000 cells from human brain tissue, researchers created the first comprehensive map of cell types involved in chronic lesions, as well as their gene expression patterns and interactions.

Dr. Reich’s team found a great diversity of cell types in the tissue surrounding chronic active lesions compared to normal tissue, and a high proportion of immune cells and astrocytes at the active edges of those lesions. Microglia comprised 25% of all immune cells present at the lesion edges.

“Our dataset is very rich. The beauty of having such a detailed map is that now we have a better understanding of the entire network of cells involved in smoldering inflammation,” said Martina Absinta, M.D., Ph.D., a former post-doctoral fellow in Dr. Reich’s lab and current adjunct assistant professor at Johns Hopkins University, Baltimore, who led the study.

More detailed analyses revealed that the gene for complement component 1q (C1q), an important and evolutionarily ancient protein of the immune system, was expressed mainly by a subgroup of microglia responsible for driving inflammation, suggesting that it may contribute to lesion progression.

To determine the function of C1q, researchers knocked out the gene in the microglia of mouse models of MS and examined the brain tissue for signs of neuroinflammation. In mice lacking microglial C1q, they found significantly decreased tissue inflammation compared to control animals. Additionally, in another group of animals, blocking C1q reduced iron-containing microglia, revealing a potential new therapeutic avenue to treat chronic brain inflammation in MS and related neurodegenerative diseases.

According to the authors, it’s possible that targeting C1q in human microglia could halt MS lesions in their tracks.

In MS, the immune system attacks myelin, a protective layer that forms around nerve cells in the brain and spinal cord, leading to vision loss, muscle weakness, problems with balance and coordination, fatigue, numbness, and other debilitating symptoms. A subset of people develop progressive MS, resulting in extensive brain tissue damage and disability. Anti-inflammatory medications help patients manage their symptoms by dampening the responses of immune cells in the blood and lymph nodes. But treatments are not as effective for patients with chronic lesions who experience ongoing brain tissue inflammation.

“We have terrific therapies that block new inflammation but nothing to stop the inflammation that’s already there,” said Dr. Reich. “In order to make strides in developing new therapies for progressive MS, we’re going to need to pick apart the cellular and molecular mechanisms one by one.”

In 2019, Dr. Reich and his team reported that damaging, chronic active lesions may be a hallmark of progressive MS. The current study identifies microglia and C1q as promising targets for progressive MS and supports the use of chronically inflamed rim lesions as an MRI biomarker for disease progression.

There is no cure for MS, and no therapies that directly treat chronic active lesions. By gaining a deeper understanding of lesion features, this study may help pave the way toward early clinical trials to test new therapies for this aspect of the disease.

This study was supported in part by the Intramural Research Program at the NINDS.

NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®