The feature image is of the villi tips in the small and large intestine that drain into mesenteric lymph notes. What was learned in the preparation of this post is that there is that B cells migrate into the villi and produce antibodies. Now we know what the white spots in the small intestines of autistic kids are that have been claimed to be “decapitated villus tips. ” We know what they are and what they are doing. These B cells may be exposed to all sorts of antigens that might eventually lead to the production of auto antibodies. B cells may also act as antigen presenting cells and migrate to other locations.
Auto immune clinics
Kevin Conners and the Conners Clinic is now an educational center. Here’s a chronic Lyme Disease youtube video. It mostly discusses Th1 and Th2 T cells and how we don’t want to activate Th1 cells in chronic Lyme Disease.
The Jeffrey Dach clinic seems to specialize in thyroid disorders.
Ty Vincent’s clinic is Global Immunotherapy. Listened to his 3min vido on Lyme Disease. His strategy seems to be to allow the bacterium to live in the host in peace and harmony without setting off the immune system.
Vijendra K. Singh is the one who discovered a connection between the mmr vaccine and autoantibodies against myelin basic protein in autism. [1] For a whle we thought that Singh might have a clinic, but I was unable to find it.
The proposed sequence of events
- dysbiosis
- toxins from the environment like RoundUp
- crappy diet, especially the Western diet
- immune system activation
- LNH, lymphocytic hyperplasia
- lymph flow directed away from the gut
- loss of disaccharidases
Revisiting Singh [1], a new auto antigen in Autism [2]
Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folic acid with overall improvements in speech, [2]
Images from ProteinAtlas
These are some ProteinAtlas links for MBP and the FRα just to have something to think about in regards to the MS and B1 cell review
Note that myelin basic protein is not expressed that much in the choroid plexus, but extensively in other parts of the brain. The folate receptor is expressed most in the choroid plexus.
Within the choroid plexus and antibody producing B cells [3]
The right image (below) is of class switching memory CSM B cell is from the Haas report. [3] While there really isn’t a lot of MBP in the choroid plexus, crossing this barrier allows for antibodies to do some damage.
The image on the right is of the folate receptor in the choroid plexus being targeted for drug delivery past the blood brain barrier. The thought process is memory B cells can migrate to places like the CSF where they will see plenty of antigen and be in the right location for the antibodies to do some damage. The image on the right is one of many illustrating targeting rapidly dividing cells via their high uptake of folic acid used for nucleotide synthesis. The folate receptor takes up folic acid via endocytosis. If B cells producing antibodies against the folate receptor were to make their way into the space between the endothelial cells and the basolateral side of choroid plexus epithelial cells. These cells have fairly tight junctions that might be destroyed by the complement system if they are bound to antibodies produced by roaming B cells. Part of this post is about gleaning from some MS reviews and speculating if B1 cells could be activated by some antigen in the gut and travel to the CNS where they could to further damage. I’m having issues finding the exact cellular makeup of the cells between capillaries and neurons in the brain. Is there an additional layer between neurons and glia of the brain and the CSF?
CNS Peyer’s Patches, aka tertiary lymphoid organs [4]
Peyer’s patches and mesenteric lymph nodes are the featured image of this post. Similar structures exist in the CNS. The meninges consists of three membranes:the dura, arachnoid mater, and the pia mater that actually comes in contact with the brain. In this figure parenchyma (of the brain) refers to glial cells and neurons.
Figure 1. Composition of CNS TLOs. TLOs in the CNS show different degrees of organization ranging from immature loose B cell aggregates (left) to highly organized lymphoid structures (right). Notably, at any time, only a minor fraction of cellular aggregates shows the highest degree of organization, however, the frequency of highly organized TLOs increases over time after onset of disease. Immature loose B cell aggregates show clustering of B cells in the meninges often in proximity to a meningeal blood vessel, scattered T cells, and a few reticulin fibers (left panel). In contrast, highly organized TLOs (right panel) are characterized by large B cell clusters next to a more or less defined T cell zone, and a dense network of reticulin fibers decorated with extracellular matrix (ECM) and chemokines. Reticulin fibers are produced by meningeal stromal cells that have differentiated into FRC-like cells. Sometimes FDCs can be detected at the center of the B cell follicle, which may have differentiated from pericytes. Plasma cells and antibodies are found in proximity to highly organized TLOs. In addition, HEVs can be detected in some highly organized TLOs, which may regulate infiltration of lymphocytes into the TLO.
Figure 2. Location of CNS TLOs. Sagittal view of the mouse brain (left) and horizontal view of the spinal cord (right) show preferential location of CNS TLOs (red stars) in association with the meninges
The Halperin review, B1 Lymphocytes in MS [5]
Step 0. Nerve damage exposing myelin basic protein and other neuronal antigens We could add ingested toxins produce epithelial cell damage and introduction to foreign antigens that resemble self.
- B1 cells are constitutively secreting natural IgM antibodies (nAbs) some of which bind to the myelin debris… or gut antigen
- B1 cells phagocytose the large, insoluble chunks of debris that may also contain oxidized lipids and citrullinated myelin basic proteins.
- Upon encounter with citrulated MBP, B1 cells produce chemo- and cytokines that recruit other immune cells like macrophage.
- The authors inserted a side note that extracellular vesicles are seen in the junction between macrophage and B1 cells. Enhanced phagocytosis and more cytokines.
- B1 cells loaded with antigens migrate to the regional lymph node to present cargo to T helper cells. How far do they migrate? Can they migrate to the CNS?
- Follicular helper T cells activate B cells (either B1 or B2 cells) in the lymph node.
- B1 cells can undergo affinity maturation
- and class-switching in germinal centers (inside lymph nodes or tertiary lymphoid organs in the
CNS) and - migrate back and forth to the brain or periphery.
- The authors depicted an active lesion in the parenchyma’s grey and white matter.
- Migratory white-matter immune cells.
- Immune cells arrive in the CSF of the lateral ventricle.
Possible causes include genetic predisposition, viral infections, smoking and diet, obesity in adolescents, exposure to toxins, geographical up bringing, and vitamin D deficiency. The authors placed this statement close to step 5 in the vicious cycle diagram.
Autoimmunity and epitope spreading [6]
The Bhagavati discussed triggers of neurological autoimmune diseases like multiple sclerosis and myasthenia gravis.
- MHC II SNP variations may predispose a person to autoimmunity by virtue of the way an antigen is presented
- Infections like EB and CMV may trigger via molecular mimicry
- Guillain Barre syndrome may be triggered by Campylobacter jejuni.
- Herpes simplex encephalitis triggers NMDA encephalitis.
- The dura mater contains lymphatics that drain into the cervical lymph nodes paving a path for CNS antigens to reach peripheral immune tissues.
- Activated memory B cells can migrate back to the CNS and get exposed to more antigen and undergo maturation to antibody presenting plasma cells and reside in meninges, lymphoid like structures.
- Germ free mice are less likely to develop experimental autoimmune encephalomyelitis EAE.
- Fecal transplants from MS patients into germ free mice can make them more susceptible to EAE.
- The antigen reactivity of a CD4+ T cell clone isolated from brain tissue of a multiple sclerosis patient showed reactivity to guanosine diphosphate (GDP)–L- fucose synthetase found in intestinal bacteria as well as to myelin
- Epitope Spreading is another explanation that involves a process that starts with the generation of an autoantibody that causes the initial injury. [7]
- A cryptic antigen is released which provoke a secondary CD4+ T cell response.[6]
- The CSF B cell population in MS is oligo clonal directed against a hetetrogenous , non-specific, and directed against ubiquitous intracellular auto-antigens that are released during tissue destruction.
References
- Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun. 1993 Mar;7(1):97-103.
- Bobrowski-Khoury N, Ramaekers VT, Sequeira JM, Quadros EV. Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention. J Pers Med. 2021 Jul 24;11(8):710. PMC free article
- Haas J, Rudolph H, Costa L, Faller S, Libicher S, Würthwein C, Jarius S, Ishikawa H, Stump-Guthier C, Tenenbaum T, Schwerk C, Schroten H, Wildemann B. The Choroid Plexus Is Permissive for a Preactivated Antigen-Experienced Memory B-Cell Subset in Multiple Sclerosis. Front Immunol. 2021 Jan 26;11:618544. PMC free article
- Mitsdoerffer M, Peters A. Tertiary Lymphoid Organs in Central Nervous System Autoimmunity. Front Immunol. 2016 Oct 25;7:451. PMC free paper
- Halperin ST, ‘t Hart BA, Luchicchi A, Schenk GJ. The Forgotten Brother: The Innate-like B1 Cell in Multiple Sclerosis. Biomedicines. 2022 Mar 4;10(3):606. PMC free article
- Bhagavati S. Autoimmune Disorders of the Nervous System: Pathophysiology, Clinical Features, and Therapy. Front Neurol. 2021 Apr 14;12:664664. PMC free article
- Vanderlugt CJ, Miller SD. Epitope spreading. Curr Opin Immunol. 1996 Dec;8(6):831-6. PMC free article
