The 17+ Benefits Of Human Immunoglobulin Therapy

Immunoglobulin Therapy For Immune Dysregulation

 
ivig therapy
 

Human immunoglobulin therapy has many benefits in treating post-infectious diseases and autoimmunity, but careful considerations must be taken into account before starting therapy.

In this post, we will discuss the benefits of human immunoglobulin therapy, its downsides, and the approved types of immunoglobulin therapies, along with its mechanism of action. 

Contents:

  1. Basics
  2. Benefits Of Immunoglobulin Therapy
  3. User Reported Experiences With Ig Therapy
  4. Types Of Immunoglobulin Therapy
  5. Short Vs. Long Term Therapy
  6. Caveats
  7. Mechanism Of Action
  8. More Research

Basics

Immunoglobulins (Ig) are antibodies derived from pooled blood donations, which predominantly consist of IgG, with minimal amounts of IgA and IgM (IgG, IgA, and IgM are explain in depth in the MOA section). R

Human Ig therapy is usually prescribed for patients with primary and secondary immune deficiency diseases and immunomodulatory therapy, for treatment of a number of autoimmune and inflammatory conditions. R

Benefits Of Immunoglobulin Therapy

1. Overrides Autoimmunity

 
t helper autoimmunity
 

 amelIntravenous Ig (IVIg) therapy can ameliorate autoimmunity by improving immune tolerance (by increasing T-regs and reducing TH1/TH17 cytokines). R

In Multiple Sclerosis (MS), Ig therapy may symptoms and possibly help with relapse (inconclusive). R R R

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic autoimmune neuropathy, affecting 4-9 people per 100,000 R

IVIg can improve CIDP symptoms and quality of life in patients with CIDP. R

IVIg also has less reported withdrawal symptoms than the treatment of CIDP with corticosteroids, although it may have higher relapse rates than corticosteroids. R

High-dose IVIG may have an anti-inflammatory effect in KD to prevent coronary aneurysm (CAA) formation. R 

IVIg may also help with Miller-Fisher syndrome and Rheumatoid Arthritis (RA). R R

2. Combats Allergies And Skin Conditions

By improving regulatory T cells (Tregs), Ig therapy may help with allergies. R

IVIg may help with atopic dermatitis by it's ability to balance TH1/TH2 cytokines. R R

For example, in a controlled study of 30 children treated with IVIG (2 g/kg/month), dermatitis symptoms were reduced 3 months after therapy. R

IVIg may also help improve symptoms of cutaneous systemic sclerosis. R

IVIg may help with Cutaneous lupus erythematosus (CLE), a chronic inflammatory autoimmune skin disease. R

3. Helps With Post Infectious Disorders

In case studies of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), Ig therapy in the short term can provide benefits. R R

Kawasaki disease (KD) is a post-infectious condition where there is inflammation in the walls of some blood vessels in the body. R

4. May Help With Tourette's and OCD

Postinfectious autoimmunity has been implicated in Tourette’s syndrome (TS) and obsessive-compulsive disorder (OCD), with low levels of IgA. R

Ig therapy has been shown to be effective in reducing tics and severity of symptoms in TS and OCD. R 

5. May Help With Chronic Fatigue And Fibromyalgia

 
chronic fatigue immunoglobulin
 

In patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS), immune dysregulation (low levels of Ig) and inflammatory factors play a huge role in their pathologies. R

Ig therapy may help improve CFS and FMS, but has only shown to be successful in very few case studies. R R

6. Improves Immunodeficiency

Ig therapy can be beneficial for immunodeficiency disorders. R

For example in those with primary immunodeficiency diseases (PIDD), patients are at increased risk of infection. R

IVIg can reduce the rates of incidences of pneumonia (bacterial or viral) and bronchitis (all types) in those with PIDD. R

Ig therapy may help with Common variable immunodeficiency (CVID) is a primary immunodeficiency with low immunoglobulins in serum. R R R 

IVIg may also help with Good Syndrome, caused by B and T cell immunodeficiency in adults. R

Ig therapy can help with primary antibody deficiencies (PAD). R

Ig therapy can also help with immunodeficiencies in children. R

7. May Help The Gut And Irritable Bowel Diseases

IVIg may help with inflammation in the gut and irritable bowel disorders (IBD). R

For example, in patients with IBD (including Crohn's Disease, ulcerative colitis, and Clostridium difficile), IVIg was able to improve symptoms and lower levels of C-reactive protein (CRP). R R

8. May Help With Neurolomuscular Disorders

Ig therapy may be beneficial for autoimmune neuromuscular disorders. R

For example, Ig therapy may help with Miller-Fisher syndrome (varient of Guillain-Barré syndrome) by improving muscular movement. R

In Myasthenia Gravis, Ig therapy has clinically shown to improve quality of life in patients. R R R

9. May Help With Alzheimer's Disease

Although, clinical trials have not shown Ig therapy alone to be effective for Alzheimer's Disease (AD), dose dependent increases in plasma and cerebrospinal fluid (CSF) Immunoglobulins are correlated with decreases in beta amyloid (Aβ) plaque levels. R

Antibodies in IVIG are able to accumulate in the central nervous system (CNS) and suppress neuroinflammation (such as neutralization of Aβ oligomers). R

10. May Be Useful For Refractory Oveitis

IVIg may act as a adjunctive therapy for refractory uveitis (inflammation of the uvea, the pigmented layer in the eye). R

11. May Reduce Seizures

Clinical data supports the role of immune mechanisms in the pathogenesis of childhood epilepsy. R

IVIg can prevent epileptic seizures by regulating cytokine pathways and antibodies that contribute to epilepsy. R

12. May Improve Autism

Low serum IgA and selective IgA deficiency has been reported in some children with autism spectrum disorders (ASD). R

Studies have failed to show improvements of IVIg therapy in ASD patients. R

13. May Help With Organ Transplants

IVIg may help with outcome of organ transplants. R R

For example, IVIg in combination with low-dose immunosuppressants was associated with a lower incidence of cytomegalovirus (CMV) disease. R

14. May Help With Sepsis

In animal models of sepsis, IVIg can help improve behavioral symptoms. R

Clarkson Disease (systemic capillary leak syndrome) is a rare disorder with episodes of transient vascular collapse, which leads to hypotensive shock, anasarca, and sepsis. R

IVIg can dramatically reduce the occurrence of systemic capillary leak syndrome attacks in most patients, with minimal side effects. R

15. May Prevent Miscarriage

 
pregnancy immunoglobulin
 

Ig therapy appears safe during pregnancy. R

In a case study, IVIg helped prevent recurrent spontaneous miscarriage (RSM). R

16. May Prevent Certain Nephropathies

In progressive immunoglobulin A nephropathy (IgAN), high-dose IVIg may be used to stop progressive loss of kidney function. R

17. May Protect Against Drug-Induced Anemia

In a case study with ceftriaxone-induced hemolytic anemia (CIHA), IVIg therapy was able to prevent drug-induced immune hemolytic anemia (DIIHA). R

User Reported Experiences With Ig Therapy

I haven't tried it, but have friends that have.

Instead, I will report on their experiences (will update). 

Types Of Immunoglobulin Therapy

Ig therapy can be taken intramuscularly, intravenously, and subcutaneously. 

For Ig replacement therapy, the usual replacement dose is 400–600 mg/kg/month,which can be given intravenously at 2–4 weekly intervals, or more frequently as subcutaneous therapy. R

For Ig therapy, a higher dose treatment, usually between 1 and 2 g/kg can be administered (usually intravenously or subcutaneously) over 2–5 days per treatment course. R

Short Vs. Long Term Therapy

Short-Term: R

  • Chronic inflammatory demyelinating polyneuropathy (also 1 study shows long term results with 1 g/kg) R
  • Guillain-Barré syndrome
  • Immune thrombocytopenic purpura
  • Kawasaki disease
  • Myasthenia gravis
  • Staphylococcal/Streptococcal toxic shock syndrome
  • Toxic epidermal necrolysis/ Stevens Johnson syndrome

Long-Term: R

  • Immunobullous disease
  • Inflammatory myopathies
  • Multifocal motor neuropathy
  • Primary immune deficiency
  • Secondary antibody deficiency
  • Specific antibody deficiency

Undefined Term: R

  • Autoimmune encephalitis
  • Pyoderma gangrenosum
  • Systemic vasculitides

Caveats

Having a clean source of Ig is paramount, as infections/pathogens/viruses can be acquired from large pools of blood - ie hepatitis C virus (HCV)'s. R R

In most clinical trials, IVIG treatment is generally safe and well-tolerated. R

Common and mild side effects of Ig therapy include hypertension, headache, malaise, nausea, low-grade fever and chills, urticaria, arthralgias, and myalgia, all which usually resolve themselves in several days. R R R

Rare, but severe side effects can occur such as neurological effects, anaphylaxis, aseptic meningitis, acute renal impairment, and thrombotic events as well as haematological manifestations. R R

IVIg resistance may occur in those with high ferritin, high neutrophil count, high C-reactive protein, low hemoglobin, low albumin levels, high aspartate and alanine aminotransferase levels, low sodium levels, high total bilirubin levels, and high gamma-glutamyl transferase and Tenascin-C levels. R R R R R R

Being obese (from high levels of inflammation) may worsen Ig therapy's outcomes. R

In preganacy, the combination of human chorionic gonadotropin (hCG) plus Ig may be a reason for unexplained recurrent spontaneous abortion (URSA), as it changes the Th17/Treg ratio. R

It may not be safe for those deficient in IgA (some cases) or for those with sepsis (some toxins may be excluded though, as seen above). R R

Ig therapy may falsely elevate blood glucose levels and may inhibit the body's natural ability to react to some infections (possibly up to a year). R R

Mechanism Of Action

 
 https://www.ncbi.nlm.nih.gov/pubmed/23411799

https://www.ncbi.nlm.nih.gov/pubmed/23411799

 

Simple:

  • Increases COX-2 R
  • Increases FCGRIIb (in macrophage/monocytes) R
  • Increases FOXP3 R
  • Increases IL-4 (decreased in T-cells) R
  • Increases IL-10 (increased in DCs, decreased in T-cells) R
  • Increases IL-33 R
  • Increases iTregs (in DCs) R
  • Increases Neutrophils R
  • Increases nTreg (in T-cells) R
  • Increases PGE2 R
  • Increases Platlets R
  • Increases Tregs (reduces TH17R R
  • Reduces ADCC R
  • Reduces CCL20 R
  • Reduces CRP R
  • Reduces ELAM-1 R
  • Reduces FCGRIA (in macrophage/monocytes) R
  • Reduces FCGR3A (in macrophage/monocytes) R
  • Reduces ICAM-1 R
  • Reduces IFN-gamma R
  • Reduces IL-1 R
  • Reduces IL-2 (in T-cells) R
  • Reduces IL-5 R
  • Reduces IL-6 (plasma cells) R
  • Reduces IL-12 (in DCs) R
  • Reduces IL-17A R
  • Reduces IL-17F R
  • Reduces IL-21 R
  • Reduces NO (from neutrophils) R

Advanced:

  • In Innate ImmunityR
    • Inhibits opsonization
    • Inhibits phagocytosis via blocking Fc receptors, induction of Fc RIIb
    • Modulates cell migration (ICAM-I, VCAM-I)
    • Reduces NO production from neutrophils
    • Inhibits monocyte activation
    • Binds activating and inhibitory Fc-gammaR
  • In Adaptive ImmunityR
    • Neutralizes microbial superantigen triggers
    • Augments regulatory T cell expression and activation
    • Provides antibodies against TCR chain, CD4, CD8, HLA, chemokine receptors
    • Fc-mediated inhibition of B cells
    • Inhibits IL-6 production required for antibody secretion by plasma cells
    • Induces apoptosis of autoreactive B cells
    • Neutralizes autoantibodies & immune complexes
    • Increases autoinantibody catabolism via FcRn
    • Provides passive immunity to combat microbial triggers
  • Overlapping Innate and Adaptive Immunity: R
    • Binds activated C1q, C3b, C4 & C3a, C5a
    • Regulates dendritic cell receptor expression & migration
    • Inhibits inflammatory cyt okines (TNF-1 , IL-1b, IL-6, IL-2, IFN- gamma)
  • IVIg in general reduces cytokines and chemokines; decreases numbers of circulating cluster of differentiation (CD) 14+ monocyte/macrophages, neutrophils and activated T cells; increases numbers of circulating NK cells; and changes in lymphocyte subsets. R
  • Some of the beneficial effects of IVIG are mediated through the Fc: 1) stimulation of an immature myeloid population of dendritic cells (DC) that secretes IL-10, which then leads to the expansion of iTreg; and 2) stimulation in an antigen-specific, HLA-restricted nTreg population that recognize the Fc of IgG. R
  • To get more specific with IgG: 
    • There are 4 human IgG subclasses (IgG1–IgG4) and most preparations consist mainly of IgG1 and IgG2 and containing much smaller amounts of the other IgG subclasses.  R
    • IgG antibodies are important for protecting the host from microbial infections, but IgG autoantibodies are also major contributors to the pathology observed in several autoimmune diseases.  R
    • The F(ab′)2 fragment (the dimeric antigenbinding fragment) is responsible for antigen recognition and plays a role in: R
      • The killing of target cells by antibody-dependent cytotoxicity (ADCC)
      • The blockade of cell–cell interactions mediated by cell-surface receptors, such as CD95 and CD95 ligand (CD95L)
      • The neutralization of cytokines
      • The neutralization of autoantibodies by anti-idiotypic antibodies
      • The scavenging of the anaphylatoxins C3a and C5a
      • Activation of follicular T helper cells, T helper 17 and T helper 1 cells that later become iTreg. R
    • The crystallizable fragments (Fc) fragment is responsible for activating the innate immune system plays a role in: R
      • The saturation of the neonatal Fc receptor (FcRn)
      • The expansion of regulatory T (TReg) cell  populations
      • The blockade of immune complex binding to low-affinity Fcγ receptors (FcγRs)
      • The modulation of dendritic cell activation via FcγRIII
      • The modulation of activating and inhibitory FcγR expression on innate immune effector cells and B cells.
      • Populaiton of glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209). R
  • IVIG can neutralize auto-antibodies by providing anti-idiotypic IgG and can delay maturation of the germinal centers. R
  • IVIg significantly enhances forkhead box protein 3-positive regulatory T cells among the memory CD4(+) T cells and IVIg inhibits the differentiation and amplification of human T(H)17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20. R
  • In neutrophils IVIG contains antibodies against siglecs expressed on the surface of neutrophils and binding to these lectins can result in cell death. R
  • Treatment with IVIg can raise platelet counts in ITP by modulating peripheral numbers of tolerizing DCs that dampen T cell responses. R

More Research

  • IVIg may help with vasculitic ulcers. R