110 Immune Disorders – Type III Hypersensitivity Reactions

Type III Hypersensitivity Reactions are characterized by the build-up of antigen-antibody (immune) complexes that overwhelm the phagocytic and recycling abilities of leukocytes such as neutrophils, monocytes, macrophages, dendritic cells, and eosinophils. This accumulation leads to immune complexes depositing in tissues such as blood vessel walls, causing irritation and inflammation, which in the case of blood vessel inflammation is known as vasculitis.  Unlike Type II Hypersensitivity Reactions, which involve antibodies binding to cells or large, non-soluble extracellular structures, Type III reactions involve antibodies binding to small, free (acellular, non-membranous) antigens to form soluble immune complexes.  These small water-soluble immune complexes are carried by the bloodstream and can readily filter out of circulation forming fluids such as synovial fluid and filtrate and thereby accumulating in joints, nephrons and other tissues.  The immune complexes predominantly involve IgG and IgM antibodies, though can “escape” phagocytosis by being small, which makes it less likely for phagocyte binding to occur.  Additionally, positively charged immune complexes are attracted into the negatively charged basement membrane of tissues, making it more likely that the immune complexes are deposited in tissues such as blood vessel walls (including those of the glomeruli), joints and skin.  Once deposited, immune complexes attract complement plasma proteins, activating the classical complement system pathway.  This activation induces mast cell degranulation and the release of pro-inflammatory cytokines and chemokines, resulting in an inflammatory response that leads to platelet activation, clotting, leukocyte recruitment, and activation, causing progressive tissue damage.

Type 3 Hypersensitivity Reactions depict the underlying pathogenic mechanism of two chronic autoimmune diseases including Systemic Lupus Erythematosus (SLE also known as lupus) and Rheumatoid Arthritis, as well as acute autoimmune disorders such as Post-Streptococcal Glomerulonephritis (PSGN), and Serum Sickness.

• Rheumatoid Arthritis (RA) is an autoimmune disease likely caused by a combination of genetic and environmental factors, with risk factors including the inheritance of certain MHC/HLA alleles, female biological sex, possibly past viral infections, physical trauma, vitamin D deficiency and smoking. RA is characterized by the deposition of immune complexes in synovial joints, particularly in the hands, feet, knees, hips, shoulders and cervical vertebrae, leading to chronic irritation, inflammation, and progressive damage.  RA can also affect other organs such as the skin, lungs, heart, blood vessels, eyes, kidneys, and liver.  Elevated levels of autoantibodies such as Rheumatoid Factor (RF) are common in RA.  Treatment typically includes nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) to reduce inflammation and leukocyte activity.

• Systemic Lupus Erythematosus (SLE), or lupus, is an autoimmune disease with unclear etiology. Risk factors include genetics (specific MHC/HLA alleles), female biological sex, and vitamin D deficiency.  SLE is characterized by elevated levels of several auto–antibodies, including anti-nuclear antibodies, leading to the progressive targeting and destruction of various tissues throughout the body.  Although there is no cure, treatments such as NSAIDs, corticosteroids, and immunosuppressants are used to slow disease progression and alleviate symptoms.  SLE signs and symptoms include a facial malar rash, fatigue, arthritis, arthralgia, myalgia, pericarditis, myocarditis, endocarditis, seizures, kidney disease, photosensitivity, dry eyes, and Raynaud syndrome (causing poor circulation in fingers and toes).  Anti-inflammatories and antimalarials, due to their immunomodulatory mechanisms, are often used to reduce symptoms and flares in SLE.

• Post-Streptococcal Glomerulonephritis (PSGN) is an acute autoimmune disorder that, as the name suggests, occurs after a streptococcal infection, typically localized to the upper respiratory tract (such as strep throat also known as streptococcal pharyngitis) or a streptococcal skin infection (such as impetigo or scarlet fever). PSGN usually develops if the Group A beta-hemolytic streptococcal infection is not promptly treated with antibiotics.  In PSGN, immune complexes between antibodies (e.g., anti-streptolysin O, anti-streptokinase) and streptococcal antigens accumulate and deposit in the glomeruli, causing irritation and inflammation, leading to hematuria, proteinuria, red blood cell casts in the urine, and potentially renal failure, indicated by oliguria, reduced glomerular filtration rate (GFR), electrolyte imbalances, acid-base imbalances, edema, azotemia, and hypertension.  Additionally, further complications can occur.  The development of autoantibodies due to molecular mimicry can lead to acute rheumatic fever (ARF) and chronic rheumatic heart disease. ARF typically develops 2-4 weeks after the initial streptococcal infection and is thought to be caused by autoantibodies that mimic streptococcal antigens, attacking proteins in the heart, joints, and/or brain. This can lead to endocarditis, myocarditis, pericarditis, migrating polyarthritis, and potentially Sydenham’s chorea, characterized by involuntary and uncoordinated movements. Immune complexes and responses can also cause skin rashes and fever, with permanent heart valve damage and myocardial scarring potentially leading to heart murmurs, arrhythmias, and reduced cardiac output.  The development of Rheumatic Heart Disease (RHD) often requires treatment involving heart valve replacement due to rheumatic heart disease.  Damage to the heart in RHD can lead to congestive heart failure (CHF), with symptoms including fatigue, exercise intolerance, dyspnea, orthopnea, edema, low cardiac output, and the increased risk of cardiogenic shock and organ failure.

• Serum Sickness is a Type III Hypersensitivity Reaction triggered by potential allergens like penicillin, antitoxins, and other drugs containing antigens that elicit an immune response.  Clinical manifestations include rashes, itchiness, urticaria, vasculitis, arthralgia, fever, glomerulonephritis, splenomegaly, hypotension, and rarely Guillain-Barré syndrome.  Prevention can involve skin testing, while treatments typically include anti-inflammatories, antihistamines, analgesics, and corticosteroids.  In some cases, plasmapheresis, which removes antigen-antibody complexes from the serum, can be an effective treatment.

*MHC/HLA = major histocompatibility complex also known as human leukocyte antigens

Summary:

• Type 3 Hypersensitivity Reactions
  • Depict the underlying pathogenic mechanism of two chronic autoimmune diseases including:  Systemic Lupus Erythematosus (SLE also known as lupus), Rheumatoid Arthritis, as well as acute autoimmune disorders including: post-streptococcal glomerulonephritis (PSGN), and serum sickness.
  • Characterized by a build-up of antigen-antibody (immune) complexes that overwhelm the phagocytic and recycling abilities of leukocytes such as neutrophils, monocytes, macrophages, dendritic cells and eosinophils.  This leads to an accumulation of immune complexes that deposit in tissues such as blood vessel walls, causing irritation and inflammation (e.g., vasculitis).
  • Unlike Type II Hypersensitivity Reactions which involve antibodies binding to cells or large, non-soluble extracellular structures, Type III Hypersensitivity Reactions involves the binding of antibodies to small, free (acellular, non-membranous) antigens to form soluble immune complexes.
  • The antibodies involved are predominantly IgG and IgM types.
  • Immune complexes “escape” phagocytosis by being small, which makes it less likely for phagocyte binding to occur.  Additionally, positively charged immune complexes are attracted into the negatively charged basement membrane of tissues, making it more likely that the immune complexes are deposited in tissues such as blood vessel walls (including those of the glomeruli), joints and skin.
  • Immune complexes attract complement plasma proteins, which bind and activate the classical complement system pathway at deposition sites.  This induces mast cell degranulation and the release of pro-inflammatory cytokines and chemokines.  The resulting inflammatory response leads to platelet activation, clotting, leukocyte recruitment and activation, leading to progressive tissue damage.
    • Affected blood vessels undergo vasculitis.
    • Affected skin exhibits urticaria, purpura (red/purple skin spot rash), skin lesions.
    • Affected kidney glomeruli become leaky, signs of glomerulonephritis and nephritis ensue
    • Affected joints exhibit synovitis, arthritis, signs include: painful, swollen joints

• • Let’s examine the autoimmune disease, Rheumatoid Arthritis (RA):
    • The cause of RA is likely a combination of genetic and environmental factors.  Risk factors include the inheritance of certain MHC/HLA alleles, female biological sex, and smoking.  RA is characterized by the deposition of immune complexes causing chronic irritation, inflammation and progressive damage in synovial joints (particularly in the hands, feet, and vertebrae) as well as other organs (e.g., skin, lungs, heart, blood vessels, eyes, kidney, and liver).  Several autoantibodies such as Rheumatoid Factor (RF) have been found to be elevated in RA.  Treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs) in order to reduce inflammation and leukocyte activity.
  • Let’s examine SLE:
    • It is unclear what causes the development of the autoimmune disease SLE.  Risk factors include genetics (inheritance of specific MHC/HLA alleles), female biological sex, and vitamin D deficiency.  SLE is characterized by elevated levels of several auto-antibodies including anti-nuclear antibodies resulting in the progressive targeting and destruction of many tissues throughout the body, particularly if not treated.  Although there is no cure, typically NSAIDs, corticosteroids, immunosuppressants are used to slow the progression and alleviate symptoms.  Signs and symptoms include facial (malar, butterfly-like) rash, fatigue, arthritis, arthralgia, myalgia, pericarditis, myocarditis, endocarditis, seizures, kidney disease, photosensitivity, Raynaud syndrome (poor circulation in fingers and toes), and dry eyes.  Treatments include anti-inflammatories and antimalarials due to their immunomodulatory mechanism which reduces signs, symptoms and flares in SLE.

• • Let’s examine PSGN
  • As the name suggests, this autoimmune disorder occurs after a streptococcal infection – which is usually localized to the upper respiratory tract (i.e., Strep throat, streptococcal pharyngitis) or a streptococcal skin infection (e.g., impetigo, scarlet fever).  For PSGN to occur, the strain of streptococcus, most often belongs to the Group A beta hemolytic strains of streptococcus.  If not treated with antibiotics promptly, PGSN can develop.  In PGSN, immune complexes between antibodies and streptococcal antigens can accumulate and deposit in the glomeruli leading to hematuria, proteinuria, red blood cell casts in the urine, and possibly renal failure which is indicated by oliguria, reduced glomerular filtration rate (GFR), electrolyte imbalances, acid-base imbalances, edema, azotemia, and hypertension.
  • In addition to antibodies that bind to streptococcal antigens, it is thought that autoantibodies develop due to molecular mimicry and that there are cross reactions that can occur that can lead to the development of acute rheumatic fever (ARF) and chronic rheumatic heart disease.
  • ARF typically develops 2-4 weeks after the initial infection with Group A beta-hemolytic streptococcus.  As mentioned, ARF is thought to be caused by the development of autoantibodies due to molecular mimicry between streptococcal antigens and proteins in the heart, joints, and brain.  This leads to the development of endocarditis, myocarditis, and/or pericarditis in addition to migrating polyarthritis, and possibly Sydenham’s chorea.  Sydenham’s chorea is characterized by involuntary and uncoordinated movements that are usually temporary due to irritation, inflammation and subsequent dysfunction of the basal nuclei within the brain.  Immune complexes and ensuing immune responses can also cause rashes on the skin and fever.  Permanent damage to heart valves, as well as scarring within the myocardium can occur, leading to the development of heart murmurs, arrythmias as well as loss of contractile strength (and reduced maximum cardiac output).  Treatment often involves heart valve replacement due to rheumatic heart disease.  Damage to the heart can cause chronic rheumatic heart disease which can lead to congestive heart failure.  Signs and symptoms of CHF include fatigue, exercise intolerance, dyspnea, orthopnea
  • Let’s examine Serum Sickness:
    • Allergens like penicillin, antitoxins and other drugs can also trigger these reactions. This is termed serum sickness and occurs when a drug contains an antigen that triggers an immune response.  Clinical manifestations include rashes, itchiness, urticaria, vasculitis, arthralgia, fever, glomerulonephritis, splenomegaly, and hypotension and rarely Guillain-Barré syndrome.   Prevention can involve skint testing and treatments involve anti-inflammatories, anti-histamines, analgesics, and immunosuppressants such as corticosteroids.  At times plasmapheresis, removing of antigen-antibody complexes from serum is an effective treatment.