See also “Hemolytic anemia” under “blood diseases” and “Hemolytic uremic syndrome” under “Kidney diseases”. See also Hypersensitivity Reactions; See also Lupus
Introduction:
Autoimmune disorders such as multiple sclerosis (MS), type 1 diabetes (T1D) and rheumatoid arthritis (RA) occur when autoreactive immune cells, especially T cells and B cells are overactivated and recruited to cause self-tissue damage. Researchers have discovered about 150 types of autoimmune diseases and adopted a series of treatment measures. The diversity and rapid rise of autoimmune diseases challenge the health care system and the entire pharmaceutical industry. Current drugs available for the treatment of autoimmune diseases are non-specific and have side-effects such as infection, allergy and malignant disease. Instead, antigen-specific immunotherapies for autoimmune diseases aim to induce tolerization toward autoantigens without suppressing the systemic immunity. See Wu
Autoimmune diseases are generally understood to be diseaes where the target of the disease is “self” or “self antigen”. Among the many types of autoimmune diseases, there are a number of diseases that are believed to involve T cell immunity directed to self antigens, including multiple sclerosis (MS), Type I diabetes, and rheumatoid arthritis (RA). Automimmune disorders are a significant clinical problem. In the US they are estimated at more than 8.5 million.
Autoimmune diseases, with the exception of rheumatoid arthritis and autoimmune thyroiditis, are individually rare, but together they affect about 5 percent of the population in Western countries. Autoimmune diseases are a poorly understood group of diseases. Mackay (New England J. Medicine, 345(5), 2001).
The autoimmune response underlying a variety of rheumatic diseases, such as with systemic lupus erythematosus (SLE), is distinguished by the production of antibodies with specificites for molecules involved in regulating the structure and assembly of nucleic acids. For example, the oncogene DEK has been shown to be an autoantigen and anti-DEK autoantibodies are associated with a distinct form of juvenile rheumatoid arthrities with iridocyclitis affecitng young girls (Wichmann, Human Immunology, 60, 1999, 57-62).
Autonomic nervous system (ANS) is the part of your nervous system that controls involuntary bodily functions such as heart rate, breathing, digestion, and blood pressure. It is divided into the sympathetic division, known as the “fight or flight” response, and the parasympathetic division, known as the “rest and digest” response. It regulates smooth muscles, cardiac muscle, and glands, operating automatically without conscious control.
Possible Triggers for Autoimmunity and Abnormalities Associated with Automimmune Diseases
Molecular mimicry can trigger self-reactive B cells to produce auto-antibodies through linked recognition. For example, antibodies produced in response to streptococcus bacteria cross-react with self-antigens in kidneys, joints and heart resulting in Rheumatic fever. How this can work is the following: When a B cells takes up and presents self antigen to a T cells, T cells do not react (reactive ones were deleted) so there is no Ig production. However, sometimes after infection self antigen gets presented along with the foreign peptide which activates T cells. B cells produce antibodies here against the self-peptide.
Bystander Activation: is due to tissue destruction caused by a pathogen which allows self-antigens to be presented in an inflammatory milieu. A DC encounters a microbe and becomes stimulated which activates a T cells. For example, in response to theilers virus which infects neurons in the brain, T cells are recruited by inflammatory mediators. Cytotoxic T cells specific for viral antigens clear the virus. However, a breakdwon in degradation of meline as a consequence of neuronal death autoimmune disease begins mediated by myelinspecific CD4+ T cells. In the first stage, the CD4+ T cells respond to a single dominant eptiope in a myelin protein. Over time, the specificity of the CR4+ T cells response spreads form just one epitope to other epitopes in the same protein and in different proteins.
Dysregulation of the Innate Immune System: If infected mice with agonist for TLR 9 no disease. However, TLR 3 or 7 were sufficient. This suggested that getting Type I IFN in vivo might be enough to break the tolerant model. IFN-alpha levels are often increased in SLE pateints. TNF-alpha is increased in RA pateints.
There is growing evidence that TLRs respond to endogenous ligands (as well as TLRs) such as fibrinogen, heat shock proteins, mammalian DNA, etc. This might suggest that the primary lesion in some autoimmune diseases is due to the failure to properly discriminate self versus non-self by the innate immune system.
Hygiene Hypothesis: Autoimmunity is a product of both genetic and environmental factors. Interestingly, there has been a steady increase in the prevalence of autoimmune diesease, allergies and inflammatory bowel disease in developed countries. Under the “hygiene hypothesis” is is proposed that microbial exposure prevents immune mediated inflammatory disease. It is beleived that microbial antigens may compete with self-antigens for antigen processing machinery and/or binding to MHC molecules. Lymphocytes proliferating to pathogens might also out-compete self-reactive T cells for cytokines and MHC intereactions needed for survival.
Counter-Regulatory Theory: states mircobial infections can induce regulatory T cells that make IL-10 and TGF-beta. There is literature reporting that DCs expressing indoleamine 2,3-dioxygenase (IDO), the rate limiting tryptophan-catalbolizing enzyme induce Treg responses and deplete responding T cells by eliminating tryptophan. (T cells can not make trypotphan, so if break it down, T cells die). Further, adminsitering certain TLR ligands for TLR9 and TLR4 induced IDO and can inhibit experimental asthma (see Rax et al.).
Susceptibility genes are shared by multiple autoimmune diseases while others are unique to a particular disease.
Depletion of Tregs: Depletion of different CD4+ T cell subsets results in manifestation of different autoimmune disease in mice. For example, depletion of mice of CD25-CD62L+ resulted in gastritis.
Aberrant expression of CD86: Several automimmune such as systemic lupus erythematosus (SLE) have aberrant CD86 expression.
Aberrant expression of chemokines: A hallmark of autoimmunity and other chronic diseases is the overexpression of chemokines, resulting in a detrimental local accumulation of proinflammatory immuen cells.
Autoantibodies: Evidence is accumulating that low levels of autantibodies occur in even healthy individuals. Thus any event that will increase their concentration may produce various degrees of pathogenicity. Among the autoantibodies identified, special emphasis has ben placed on anti-DNA antibodies. Anti-DNA antibodies are known to be tightly correlated with systemic lups erythematosus (SLE). They tend to fluctuate with disease activity, and high anti-DNA serum titers are often associated with kideny damage. DNA is typically an intracellular component. However, peripheral blood cells can excrete DNA and DNA has been associated with their plasma membrane fraction. DNA receptors have also been described in human platelets and would appear to have a functional role, as their associated with DNA leads to platelet aggregation and serotonin release. Keyhani (Transplantation Proc. 27(5) 1995) isolated DNA associated with Wil2-NS (a non-immunoglobuline secreting human B lymphocyte line) and showed the role of this pmDNA. They did this by studying the presence of IgG in the sera of pateints with various autoimmune diseases directed against Wil2-NS pmDNA.
Treatment Strategies Generally
Self tolerance is though to be kept in check by four main mechanisms: central deletion fo high-avidity autoreactive T or B cell clones; peripheral delection or functional inactivaiton of autoreactive thymic T cell or bone marrow derived B escapees; exportation of mature regulatory T (Treg) cells form the thymus and de novo generation of R reg or regulatory B cells in the periphery. Sera “Antigen-specific therapeutic approaches” Nature Biotechnology, 37, 2019, 238-251)
DNA vaccines: DNA vaccination invovles the transient expression fo antigens in uninfalmed tissues using DNA vectors. For example, DNA vaccination of patients recently diagnosed with type 1 diabetes with an insulin encoding plasmid decreased the peripheral frequency of insulin reactive CD8+T cells and preserved C peptide levels. In another phase 1/2 trial, a DNA vaccine encoding myelin basic protein (MBP; BHT-3009; Bayhill Ehterapeutics) was well tolerated in pateints with MS). Sera “Antigen-specific therapeutic approaches” Nature Biotechnology, 37, 2019, 238-251)
Whole antigens: Clinal testing of whole-antigen immunotherapties autoimmunity have generally been met with failure. Sera “Antigen-specific therapeutic approaches” Nature Biotechnology, 37, 2019, 238-251).
Cell based immunotherapy: Several gruops have used antigen coupled syngeneic lymphoic dells and erythrocytes to promote dominant tolerance. Sera “Antigen-specific therapeutic approaches” Nature Biotechnology, 37, 2019, 238-251)
Nonoparticles for antigen delivery: Nanoparticles have been used as vehicles for antigen delivery to APCs. Sera “Antigen-specific therapeutic approaches” Nature Biotechnology, 37, 2019, 238-251)
Dendritic cell transfer: Specific subsets of DCs support immune tolerance through the generation fo anergic T cells and/or antigen-speciific Treg cells. Sera “Antigen-specific therapeutic approaches” Nature Biotechnology, 37, 2019, 238-251)
Specific Types of Autoimmune Diseases
Addison’s disease is a rare endocrine disorder characterized by an insufficient synthesis of the steroid hormones cortisol and aldosterone by the two outer layers of adrenal gland cells (adrenal cortex), resulting in adrenal insufficiency. Chronic adrenal insufficiency or Addison’s disease is due to autoimmune etiology in 80% of cases. It can be present as an isolated autoimmune adrenal deficiency or as part of the aforementioned autoimmune polyglandular syndromes: PAS type I or type II. PAS type I results from the mutation of the AIRE gene located on chromosome 22q22.3. PAS type I is unrelated to HLA genes. The most frequent association of Addison’s disease is within PAS II, having HLA-DR3 or HLA-DR4 or both as a genetic substrate. The main autoantibodies involved in triggering adrenal autoimmunity are anti-21-hydroxylase antibodies.
Alopecia areata (AA) is an autoimmune disease, the second most common, after androgenic alopecia. Clinically, it is characterized by non-scaly, non-inflamed, hairless macules, and more frequent lesions on the scalp and chin, but other regions can also be affected, such as the eyelashes or eyebrows. The prevalence of the disease is 1 in 1000 and the incidence is 2% globally. Most of the patients diagnosed with this pathology are young, under 30 years old, and only approximately 20% fall into the over-40 age category.
Anti–glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects glomerular capillaries (where it may result in glomerular necrosis and crescent formation), pulmonary capillaries (where it may cause alveolar hemorrhage), or both. It is characterized by the presence of circulating and deposited antibodies directed against
basement membrane antigens, and as such is classified an immune-complex small vessel vasculitis in the Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.
Antiphospholipid syndrome (APS): show clinical manifestations of severe predisposition to thrombosis. Ritis (J. Immunology, 2006, 177: 4794-4802) show that antiphospholipid Ab induced complement activaiton and downstream signaling via C5a receptors in neutrophils leads to the induction of Tissue Factor (TF), a key initiating component of the blood coagulation cascade.
Autoimmune Thyroid Disease:
The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto’s thyroiditis). Hashimoto’s thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. Meanwhile, autoantibodies against the TSH receptor have been found in Graves-Basedow disease. Numerous susceptibility genes, as well as epigenetic and environmental factors, contribute to the pathogenesis of both diseases.
Autoimmune thyroid diseases occur in 17% to 30% of patients with type 1 diabetes. The close relationship between these conditions is largely explained by the sharing of a common genetic background. HLA antigens DQ2 (DQA1∗0501-DQB1∗0201) and DQ8 (DQA1∗0301-DQB1∗0302), closely related to DR3 and DR4, are the common predisposing factors. See Cavalu
Graves’ Disease: is the attachment of autoantibodies to receptors on the thyroxin secreting follicle cells of the thyroid gland. The abnormal stimulation of these cells causes the overproduction of this hormone and the symptoms of hyperthyroidism, which affect nearly every body system.
The immunologic processes involved in Graves’ disease (GD) have one unique characteristic – the autoantibodies to the TSH receptor (TSHR) – which have both linear and conformational
epitopes. Three types of TSHR antibodies (stimulating, blocking, and cleavage) with different
functional capabilities have been described in GD patients, which induce different signaling effects varying from thyroid cell proliferation to thyroid cell death. In Graves’ disease (GD), the main autoantigen is the thyroid stimulating hormone receptor (TSHR), which is expressed primarily in the thyroid but also in adipocytes, fibroblasts, bone cells, and a variety of additional sites including the heart. The TSHR is a G-protein coupled receptor with 7 transmembrane-spanning domains. TSH, acting via the TSHR, regulates thyroid growth and thyroid hormone production and secretion. The TSHR undergoes complex post-translational processing involving dimerization and intramolecular cleavage; the latter modification leaves a 2-subunit structural form of the receptor which eventually undergoes degradation or shedding of the ectodomain. Each of these post-translational events may influence the antigenicity of the receptor and, furthermore, this complex processing may contribute to a break in self-tolerance. For example, the affinity of TSHR antibodies for the TSHR ectodomain is greater than for the holoreceptor itself. See Davies
Graves’ disease (GD) is an organ-specific autoimmune disorder of the thyroid due to the presence of circulating anti-thyroid-stimulating-hormone receptor (TSH-R) stimulating autoantibodies that lead to hyperthyroidism. It is caused by the breakdown of immune tolerance against thyroid antigens, in particular against the TSH receptor, and it is characterized by thyrotoxicosis, the presence of serum antithyroid antibodies (ATA), as well as of autoreactive lymphocytes in the gland. See Martina
Clinical manifestations are associated with hyperthyroidism, but also with the autoimmune process. Thyroid hormones excess affect several different body systems, and for this reason, signs and symptoms associated with GD can vary strongly, and significantly influence the general well-being. Common symptoms are: tremor, heat sensitivity and warm, weight loss even if with normal eating habits, anxiety and irritability, enlargement of the thyroid gland (goiter), alterations in menstrual cycles.
Antithyroid drugs are the first-line therapy for GD in Europe and are increasingly preferred compared to radioiodine in North America. Ablative therapy, either from radioactive iodine or surgical thyroidectomy, can cause hypothyroidism and leads to lifelong thyroid hormone replacement.
Hashimoto thyroiditis: is an autoimmune disease characterized by hypothyroidism and a high level of anti-thyroid autoantibodies. HT is the most common autoimmune disease in reproductive age women. The two autoantibodies associated with autoimmune destruction of the thyroid gland and with the clinical condition of hypothyroidism are the antithyroid peroxidase antibody (TPOAb) and the anti-thyroglobulin antibody (TGAb). See Ortiga
Guillain-Barré syndrome:
Guillain-Barré syndrome is the most common and most severe acute paralytic neuropathy, with about 100 000 people developing the disorder every year worldwide. Under the umbrella term of Guillain-Barré syndrome are several recognisable variants with distinct clinical and pathological features. The severe, generalised manifestation of Guillain-Barré syndrome with respiratory failure affects 20–30% of cases. Treatment with intravenous immunoglobulin or plasma exchange is the optimal management approach, alongside supportive care. See Dorne
Guillain-Barré syndrome is usually preceded by infection or other immune stimulation that induces an aberrant autoimmune response targeting peripheral nerves and their spinal roots. Two-thirds of adult patients report preceding symptoms of a respiratory or gastrointestinal tract infection within 4 weeks of onset of weakness. Molecular mimicry between microbial and nerve antigens is clearly a major driving force behind the development of the disorder, at least in the case of Campylobacter jejuni infection. However, the interplay between microbial and host factors that dictates if and how the immune response is shifted towards unwanted autoreactivity is still not well understood. The acute progression of limb weakness, often with sensory and cranial nerve involvement 1–2 weeks after immune stimulation, proceeds to its peak clinical deficit in 2–4 weeks.
The neural antigens targeted by GBS vary with disease phenotype. The axonal variants of GBS most commonly target gangliosides. Gangliosides are sialic-acid–containing glycosphingolipids that are present in peripheral nerve fibers. Gangliosides facilitate cell-cell interactions between neurons and glia, modulate receptors, and regulate growth. The phenotypic expression of GBS often depends on the anatomic distribution of the gangliosides to which the antiglycolipid antibodies bind, as well as the binding specificity of these antibodies. The lipooligosaccharides of Campylobacter jejuni, the most common antecedent infection in GBS, contain ganglioside-like moieties. Molecular mimicry in the production of antiganglioside antibodies is well established in acute motor axonal neuropathy and the Miller-Fisher variant, as evidenced by multiple observations. ISee Sun
When patients present with rapidly progressive paralysis, the diagnosis of Guillain-Barré syndrome needs to be made as soon as possible. Although establishment of the diagnosis in typical cases is usually straightforward, there are many clinical and investigative components to consider, especially in atypical cases. The diagnosis is largely based on clinical patterns, because diagnostic biomarkers are not available for most variants of the syndrome. Identification of biomarkers and establishment of their pathophysiological roles, if any, in experimental models has been a major research challenge. See Dorne
Typically, GBS presents as an ascending, symmetric sensorimotor variant, beginning with distal paresthesias and progressing to lower-extremity weakness before spreading to the upper extremities and cranial nerves. However, the disease exhibits a broad phenotypic spectrum. Symptoms typically begin about 10 days after an antecedent trigger, often an infection, and reach a nadir within 2 weeks. A nadir within 24 hours or progression beyond 4 weeks should raise suspicion for an alternative diagnosis. The disease usually plateaus in 1 to 4 weeks. The classic sensorimotor GBS manifests approximately 10 days after the antecedent event. The initial symptoms include lower back pain from nerve root inflammation and distal paresthesias (acroparesthesias). The characteristic symmetric weakness involving proximal and distal muscles results from involvement of both proximal nerve roots and distal nerves (polyradiculoneuropathy), where the blood-nerve barrier is weakest. See Sun
Intravenous immunoglobulin and plasma exchange are equally efficacious treatments for GBS. This condition is typically monophasic, but patients may experience treatment-related fluctuations. Respiratory insufficiency and cardiovascular compromise are the most critical complications that may require care in an intensive care unit (ICU). Some complications are hospital-acquired, such as infections. Patients with bulbar palsy have swallowing difficulty, and those with facial palsy may develop corneal ulceration. Extremity weakness may lead to contractures, and prolonged immobility may result in deep venous thrombosis. Autonomic dysfunction may manifest with bowel and bladder dysfunction. Pain, anxiety, and hallucinations are often underrecognized and undertreated, especially when patients have difficulty communicating or are in the ICU. Interprofessional management of complications is important and should include clinicians, nurses, occupational therapists, physical therapists, speech therapists, and dietitians. See Sun
Primary Immune Thrombocytopenia (ITP)
ITP is an autoimmune diesease medaited by antiplatelet antibodies that cause opxonization of platelets and elimination through binding to FcyR-bearing phagocytic cells and subsequent phagocytossi. In additionk the same autoantibodies bind to megakaryocytes and impair platelet prodution. The annual incidince of ITP in the US is about 16000 cases. Although the thrombocytopenia in ITP can be severe, most patients have only minor signs of bleeding. Persistently low platelet counts (<20 x 106/L) however, are associated with an increased risk of serious bleeding, such as intracranial hemorrhage. The inital treatment for ITP is cortisoteroids, IVIg or intravenous RhD immune globulin (anti-D). These compoudns act primarily by interfering with platelet destruction and cytokine modulation. Rozrolimupad, a mixture of 25 recombinant fully human RhD specific mAbs represents a first in class of recombinant human monoclonal antibody mixtures that can be produced independently of human plasma supply. Robak, Blood, 120(18):3670-3676
Myasthenia gravis (MG):
MG is an autoimmune and neurological disorder that affects about 200-400 people per million.
Myastehnia gravis (MG) is a neurological B cell mediated autoimmune disorder affecting the nueromuscular junction. (Vanoli “Ravulizumab for the treatment of myasthenia gravis” Expert Opinion on Biological Therapy” 2023, 23(3).)
Symptoms
MG is characterized by muscle weakness and fatigability that worsens after their use. Pateints experience muscle weakness and symptoms including drooping eyelids, double vision and slurred speach. For the majority of patients, initial symptoms manifest in the extrinisic ocular muscles of the eye.
A quarter of patients with MG will progress to myasthenic crisis in which paralysis of the respiratory muscles occurs. In such cases, assisted ventilation is required to sustain the life of the affected patients. (Rother, US 15/282,464).
Causes
MG can result from immune mediated loss of acetylcholine receptors at neuromuscular junctions of skeletal muscle. A large number of patients with MG express antibodies that bind to and inhibit the activity of the nicotinic aceytlcholine recptor (AChR). The antibodies cause loss of acetylcholine receptors and diminished receptor function at the muscle end-late of the nature neuromuscular junction. (Rother, US 15/282,464) Close to 90% of MG patients have antibodies to the AChR. Binding of these antibodies to the receptor results in the failure of skeletal muscle to respond appropriately to nerve stimulation owing to antibody induced injury of the postsynaptic muscle surface. (Kusner, “effector of complement and regulation on myasthenia gravis pathogenesis” Future Drugs Ltd, 2008).
About 80% of patients with MG produce acetylcholine receptor autoantibodies. The other 20% do not, but they do experience the same MG symptoms. Many of the 20% of MG patients without acetylcholine receptor autantibodies instead generate autoantibodies to a membrane protein called MuSK, a specific muscle recptor tyrosine kinase. Athena diagnostics v. Mayo (US Ct Appeals Fed. Cir, 2019). Most patients (about 85%) display antibodies directed against the nicotinic acetylcholine receptor (AChR), whereas only 9% present antibodies anti-muscle-specific kinase (muSK) and 1% have antibodies anti-lipoprotein-receptor related protein 4 (LRP4). Anti-AChr antibodies are mainly of IgG1 and IgG3 subclass, and thus able to activate the complement cascade which is the main pathogenic mechanism of AChR+ MG. Complement activation ultimately leads to the disruption of the postsynaptic folds with loss of dispersion of AChRs. Another important pathogenic mechanism is antigenic modulation, where bivalent antibodies crosslink AChRs with acceleration of AChR endocytosis and degradation. Finally, anti-AChR antibodies act also by directly blocking the acetylcholine binding site on AChRs. Anti-MuSK antibodies, on the other hand, are of IgG4 subclass and thus unable to activate complement cascade and induce antigenic modulation as they are funcitonally monovalent. Their pathogenic effect is exerted by masking the binding sites in MuSK that interact with LRP4 and collagen Q, which is essential for AChR clustering. Indeed, the inactivation of MUSK leads to a decrease of AChR density and an impairment of their alignment on the postsynaptic membrane. Anti-LRP4 are of IgG1 subclass and are thus able to activate the complement cascade. Moreover, these antibodies also inhibit AChR clustering, by blocking the agrin-LRP4 interaction. Finally, a small percentage of MG patients are defined as serongegative, as no specific pathogenic antibody has been identified. Vanoli “Ravulizumab for the treatment of myasthenia gravis” Expert Opinion on Biological Therapy” 2023, 23(3).)
The activation by antibody ultimately leads to formation of the membrane attack complex (MAC) that produces cell lysis and, in Mg, produces focal damage of the postsynaptic surface of of the muscle, which ultimately compromises neuromuscular transmission. (Soltys, “Extraocular muscle susceptibility to myasthenia gravis” Ann. Ny.Y. Acad. Sci, 1132, 220-224, 2008).
Pathophysiology of complement activation in MG:
Anti-acetylcholine (Ach) recetpor (AChR) antibodies activate the complement cascade through the classical pathway by bnidng C1q on the Fc domain. The subsequence formation of C5 convertase initiates the teminal pathway which ultimately leads to the formation of the membrane attack complex (MAC), a lytic pore on the posynaptic membrane. The final effect is a focal lysis of the neuromusclar junction with disruption of the postsynaptic folds and loss of AChRs. Antibodies such as Ravulizumab (see below) binds with high affintiy to C5, inhibiting the enzymatic clevage and thereby preventing the MAC formation. Vanoli “Ravulizumab for the treatment of myasthenia gravis” Expert Opinion on Biological Therapy” 2023, 23(3).)
Symptoms:
The typical clinical feature of MG is muscle weakness that fluctuates and worsens with active muscle use, and improves with rest. Initial weakness often starts with extraocular muscles [Ocular MG (OMG)], with a classic presentation of intermittent drooping of the upper eyelid (ptosis) and rapidly progressive double vision (diplopia). In ~15% of patients, the symptoms remain ocular, however, for the majority of patients (85%) symptoms progress to limb and bulbar muscles, resulting in generalized MG (GMG), usually within the first 2 years. Respiratory muscles can also be affected. It is interesting to note that weakness in myasthenia can be alleviated by applying cold on the weak muscle thus blocking the effect of acetylcholine esterase and improving strength. This is the basis of the ocular ice-test. The OMG without anti-AChRAbs generally is a harbinger of a milder disease, if it does not become generalized in the first 2 years. Thymic abnormalities (thymoma-associated MG; TAMG) are common in GMG patients with almost 50% having thymic hyperplasia, and 10–15% having a thymic tumor. ee Ogar
Gender and age at onset also play a critical role in AChR MG pathogenicity. The disease has two typical peaks of onset; early-onset MG (EOMG, <50 years), with a predominance of females and late-onset MG (LOMG, >50 years), that have a larger proportion of males. See Ogar
Diagnosis:
MG patients are subgrouped based on the presence of Abs as well as their clinical phenotypes, thymus pathology, and age at onset. Antibody testing has a crucial role for clinical diagnosis confirmation and treatment. Majority of MG patients (around 80–85%) develop Abs against the acetylcholine receptors (AChR; AChR MG), whereas muscle-specific kinase Abs (MuSK; MuSK MG) are detected in 1–10% patients, depending on detection techniques used and the differences between the source population. ee Ogar
For the past several years, the radioimmunoprecipitation assay (RIPA) method has been the gold standard test for the detection of AChRAbs, with nearly 100% test specificity. That is, if the patient with muscle weakness tested positive for AChRAbs by RIPA, clinical diagnosis of MG can be confirmed. Human AChR used in RIPA is usually obtained from human muscles or AChR-expressing cell lines, such as TE671 cell line (that expresses fetal AChR), or CN21 cell line, (that expresses both fetal and adult AChR). The RIPA is based on the labeling of human AChR antigens with 125I-α-bungarotoxin and then precipitating the complex of labeled AChR-with patients AChR binding Abs using a secondary antibody “in solution.” The precipitate is counted and compared with healthy control serum. If the test result is positive then, blocking with cold α-BT (unlabeled) is performed to verify binding results. e Ogar
Treatment:
Autoimmune attack is dependent on T cells, resulting from loss of tolerance toward self antigens at the level of the tymus. However, Abs and complement are key effectors of the loss of possynaptic AChRs and associated desstruction of the NJM. Therefore, the goal of MG treatment is to interrup the autoimmune prcoess by T cells and B cells using corticosteroids, thymectomy, IVIg and immunosuppressants. (Kim, J. Clin. Neurol 2011; 7: 173-183).
MG is characterized by remarkable clinical variability, and no one treatment can be predicted to have the same beneficial (or toxic) effect on all patients. (Sanders, Autoimmunity August -September 2010, 43 (5-6), 428-435).
–Anti-C5 (eculizumab, Ravulizumab, etc):
Andrien (US 2017/0298123) discloses that BNJ441 (“Ravulizumab”) relative to exulizumab contains four amino acid substitutions in the H chain, Tyr-27-His, Ser-57-His, Met-429-Leu and Asn-435 Ser (note that positions 429 and 435 of BNJ441 correspond to positions 428 and 434 uner the EU numbering system). These mutations were engineered to enable an extended dosing interval verus exulizumab by increasing the circulating half-life by reducing antibody clearance and increasing the eficiency o f the FcRn-medaited antibody recylcing. Adrian teaches that the antibodies are useful for treating a variety of complement associated disorders such as aHUS, PNH and myasthenia gravis.
Bedrosian (US Patent Application NO: 15/595,890, published as US 2017/0342139) discloses methods of treating myasthenia gravis (MG) in a patient positive for auto-antibodies binding to nicotinic acetylcholine receptor by administering eculizumab using a phase dosing schedule with an induction phase comprising 900 mg on day 1, 900 mg odses on days 7, 14, and 21 and 1200 mg as a fifth induction dose on day 28 wherein the patient is administered eculizumab for at least 26 weeks and wehrien the 28 day induction phase of eclizumab is followed by a minatenance phase of 1200 mg of eculizumab 14 days after the fift induciton dose and 200 mg eveyr 14 days therafter. 60 kg, 3300 mg to a patient weighing 60-100 kg or 3600 mg to a patient weighing greater than 100 kg.
Fujita (US Patent Application No: 16/791,415, published as US 2020/0331993) discloses a method of treating myasthenia gravis (MG) with an anti-C5 antibody such as Ravulizumab (also known as antibody GNJ441, ALXN1210 or Ultomiris) based on weight. At day 1, 2400 mg to a patient weighing 40-60 kg, 2700 mg for a pateint weighing 60-100 kg and 3000 mg for a patient weighing greater than 100 kg. On day 15 and every 8 weeks thereafter a miantenance dose of aslo based on weight; 3000 mg to a patient weighing 40-
Rother (US Patent Application No: 15/282,464, published as US 20170015740) discloses compositions containing an inhibitor of the complement component C5 such as the antibody eculizumab sold by Alexion Pharmaceuticals for treating MG. In one embodiment, the anti-C5 antibody is adminsitered at a doese of about 600 mg every week for two or more weeks followed by 900 mg about every 14 days.
(NIHR Horizon Scanning Research & Intelligence Center “Eculizumab (Soliris) for refractory myasthenia gravis, March 2016. discloses eulizumab adminsitered IV at 1,200 mg every 2 weeks according to a schedule of randomised 900 mg IV once weekly for 4 weeks, followed by 1,200 mg IV every 2 weeks for weeks 5-26 for treatent of MG
Zhou (“anti-C5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis” J. Immunol. (2007) discloses that in rats induced with AChR Ab, an anti-C5 mAbrestored strenght in two thirds of the rats.
–Immunosuppressive drugs:
Most nuerologists consider some form of immunosuppression to be essential to the treatment of MG, however, there is no general concensus about which drug should be used, in which patients, and when. Corticosteroid exert profound immunosuppression by inducing T lymphocyte apoptosis, repressing transcription of inflammatory cytokines and impairing DC maturation. Corticosteroid were the first immunosuppressants used in MG therpay and are still used (i.e., prednisone) in most patients tarting with high daily doses adn then shifting to alternate day adminsitration. Remission (30%) or marked improvement (45%) occurs isn over 3/4 of patients, a further 15% have some lesser degree of improvement. (Sanders, Autoimmunity August -September 2010, 43 (5-6), 428-435)
–Thymectomy:
Thymoma is reprotedly found in 10-30 of patients with MG. Thymectomy is associated with clinical improvement in 85% of cases and 35% of pateints appear to ahve complete remission. Thymectomy is used in non-thymomatous myasthenia to improve symptoms and in the hope of reducign subsequent drug burden. (NIHR Horizon Scanning Research & Intelligence Center “Eculizumab (Soliris) for refractory myasthenia gravis, March 2016.
Other Diseases:
Narcolepsy:
Narcolepsy is thought to be an autoimmune disorder where the immune system destroys certain brain cells that produce a peptide called heptocritin. Symptoms include excessive daytime sleeping and cataplexy (muscles become suddently weak or lymph).
The FDA has approved the drug Xyrem for treatment of Narcolepsy. However, because this product contains gamma hydroxybutyrate (GHB) it is classified as a Schedule III depressants. 21 CFR 1308.13 and one must register to receive the drug.
Neuromyelitis optica spectrum disorder (NMOSD): is an autoimmune disorder characterized by the presence of serum anti-aquaporin-4 (AQP4) autoantibody, recurrent optic neuritis (ON), and myelitis in most cases. Unlike MS, neurologic disability in patients with NMOSD typically accumulates with each clinical episode. See Aoki
Hereditary angioedema (HAE): is a disease caused by deficiency of the CP control protein, C1-Inh. These individuals have recurrent swelling in the extremities, face, lips, larynx or GI tract. The patients suffer form a felling of fullness but not pain or itching in the affected area except for those with abdominal swellings who often experience acute abdominal pain. The latter two presentations are of the most concern because suffocation can occur if the airways are obstructed, and the acute swelling of the abdominal region produces intense pain often resulting in exploratory surgery. The mechanisms for production of the swelling involves not the complement enzymes, but the kinin-generating pathway. It is the product of Bradykinin through this pathway that is responsible for the tissue permeability changes that cause the swelling. Acute trematnets include C1 inhibiotr (C1-INH, Berienrt) or a replacement thrapy; ecallntide, a kallikrein inibitor;a nd icatibant, a bradykinin-2 receptor antagonist. Prophylactic treatments include attenuated adrogens and C1 inhihibor. (US Patent Applicaiton No: 15/895,551, published as US 2019/0247560).
Primary biliary Cholangitis (PBC): is an autoimmune disease in which the bile ducts are inflamed and slowly destroyed. It previously was called primary biliary cirrhosis. Bile is a fluid made in the liver. It helps with digestion and absorbing certain vitamins.
–treatment:
—-Linerixbat (GlaxoSmith) is an investigational product for the treatment of cholestatic pruritus in patients with primary biliary cholangitis (PBC): Cholestatic pruritus causes an internal itch that cannot be releived by scratching. Linerixbat is a minimally absorbed small molecule inhibitor of an ileal bile acid transporter (IBAT), adminsitered as an oral tablet.
Celiac Disease:
Celiac disease is a serious autoimmune disease that occurs in genetically predisposed people where the ingestion of gluten leads to damage in the small intestine. It is estimated to affect 1 in 100 people worldwide, but only about 30% are properly diagnosed. Gluten is a dietary staple that is a leading environmental trigger for the development of celiac disease. Patients with celiac disease show hypersensitivity toward cereal gluten proteins, leading to lesions within the digestive system.
Although it was originally considered a food hypersensitivity disorder, CeD shows many similarities to tissue-specific autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis. Typical autoimmune features include a strong human leukocyte antigen (HLA) association, production of specific autoantibodies, and immune-mediated killing of a particular cell type (enterocytes). Still, CeD is unique among autoimmune conditions, as the disease only manifests upon exposure to an exogenous factor. This foreign pathogenic driver constitutes a range of related cereal proteins known collectively as gluten.
In active CeD, the turnover rate of enterocytes is increased as the proliferative index is doubled compared with the healthy state. Ninety percent of the differentiated epithelial cells in the human duodenum are enterocytes. These cells take up nutrients from the gut lumen, but the cells are also involved in nonabsorptive functions such as transport of polymeric immunoglobulins into the gut lumen. Other types of epithelial cells are goblet cells, Paneth cells, tuft cells, and hormone-secreting enteroendocrine cells. All these cells are generated from intestinal stem cells that are localized in specialized niches at the bottom of the crypts and that are hallmarked by expression of leucine-rich repeat-containing G protein–coupled receptor 5 (Lgr5). Once generated, the newly formed cells migrate to the tips of villi, where they are extruded 4–6 days later. It has been estimated that in humans, 1011 epithelial cells (∼200 g) are shed every day.
–Diagnosis: A diagnosis of celiac disease needs confirmation from positive serology involving IgA anti-TG2 and anti-endomysial antibodies, together with villous atrophy observed via a small intestinal biopsy. Transglutaminase 2 (TG2) is an enzyme involved in tissue repair, but in certain diseases, such as celiac disease, it can trigger harmful immune reactions. e Javed
–Treatment:
—-Ordesekimab: is a mAb that inhibits the action of IL-15. It is being investigated for the treatment of celiac disease and is being developed by Amgen in collaboration with Provention Bio, Inc.
—-Tregs: The evaluation of Tregs and TG2 inhibitors as therapeutic options is grounded in their critical roles in immune regulation and disease pathology. Tregs are key mediators of immune tolerance, capable of suppressing aberrant immune responses that drive chronic inflammation and autoimmunity. Therefore, enhancing Treg function or numbers can restore immune balance and reduce tissue damage. e Javed
—-TG2 inhibitors: TG2 is an enzyme involved in the post-translational modification of proteins and has been implicated in promoting inflammation, fibrosis, and autoantigen formation in various diseases. Inhibiting TG2 activity may interrupt these pathological processes, thereby limiting disease progression. The critical function of TG2 in the pathogenesis of celiac disease involves gluten peptide deamidation, through which it promotes antigenic presentation along with increased gluten-reactive T cells. Research shows that blocking TG2 represents an active approach for treating celiac disease. See Javed
Sjögren’s syndrome (SS) is a systemic and chronic autoimmune disease characterized by inflammatory reaction of exocrine organs including but not limited to lacrimal and salivary glands that lead to the drying of the mouth, eyes, respiratory tract, and vagina eventually. The prevalence and incidence of SS is about 0.01–0.72% and 0.003–0.011% in the population, respectively. The gender difference and clinical features are obvious for SS, the ratio of female to male patients is about 10:1 and female patients have more serious clinical manifestations.
–Treatment:
—–Antibodies: AMG 329 (Amgen): is a fully human mAb that binds and neutralizes FLT3 ligand, thereby reducing both conventional and plasmacytoid DCs that is being investated for teh treamtnet of Sjogren’s disease.
Severe Aplastic Anemia (SAA): is a rare, life-threatening blood disorder where the bone marrow stops producing enough new red cells, white cells, and platelets, leading to severe fatigue, frequent infections, and dangerous bleeding, classified by very low blood counts and a nearly empty marrow. It’s often autoimmune, attacking marrow stem cells, and requires intensive treatment like stem cell transplants or powerful immunosuppressants to restore blood production and prevent fatal complications, notes the National Marrow Donor Program (NMDP).
Severe aplastic anemia (SAA) is generally considered an autoimmune disease, where the body’s own immune system (specifically T-cells) mistakenly attacks and damages the hematopoietic stem cells in the bone marrow, preventing it from producing enough new blood cells. While its exact cause isn’t always clear (idiopathic), the most common underlying reason is this autoimmune attack, making immunosuppressive therapy a standard treatment.
Severe aplastic anemia (SAA) is not the same as hemolytic anemia (see outline); they are distinct conditions with different root causes, though both lead to anemia (low red blood cells) and can sometimes occur together or mimic each other. Aplastic anemia involves bone marrow failure (inability to produce enough cells), while hemolytic anemia involves red blood cells being destroyed faster than they can be made.
Autoimmune inflammatory myopathies:
Dermatomyositis: is an autoimmune inflammatory disease that affects muscle and skin. Symptoms include proximal muscle weakness such as problems climbing stairs and raising arms. It is usually symmatric with gradual onset. Hallmark skin findings include purple discoloration around the eyes, raised, scaly bumps on knuckles and rash over shoulders/upper back. It is due to the immune system attacking attacking small blood vessels in the musle.
–treatment:
—-Antibodies:
——ILT7: Daxdilimab (Amgen) is a fully human mAb against ILT7 that depletes certain DCs. It is being investigated for the treamtent of both dermatomyositis and anti-syntetase inflammatory myositis and discoid lupus erythematosus.
Polymyositis: is a chronic connective tissue disease characterized by painful inflammation and degeneration of the muscles; dermatomyositis is polymyositis accompanied by skin inflammation. These diseases result in disabling muscle weakness and deterioration. The weakness typically occurs in the shoulders and hips but can affect muscles symmetrically throught the body. Polymyositis and dermatomyositis usually occur in adults from ages 40-60 or in children from ages 5-15. Women are twice as likely as men to develop either disease. The cause is unknown although viruses or autoimmune reactions may play a role. Cancer may also trigger the diases. Symptoms, which may begin during or just after an infection, include muscle weakness (particularly in the upper arms, hips, and thighs), muscle and joint paint, Raynaud’s phenomenon, a rash, difficulty in swallowing, a fever, fatigue, and weight loss. In dermatomyositis, rashes tend to appear at the same time as periods of muscle weakness and other symtpoms.