HC35: Infections and autoimmunity

Overlap

Infection, inflammation and autoimmune diseases can overlap, but this isn’t necessary:

• In case of rheumatoid arthritis, there is inflammation but no infection
• In case of cholera and tetanus, there is infection but no inflammation
• In case of myasthenia gravis, there is autoimmunity but no inflammation

From infection to autoimmunity:

Infection can lead to autoimmunity. An infection induces a normal immune response, but the immune molecules or cells react with self-antigens which are similar to those of the pathogens → cross-reactivity. This can be caused by some microorganisms having qualities that resemble human qualities → normally the body doesn’t react to self-antigens due to positive and negative selection. This is called tolerance, which is expressed by the regulatory T-cells.

Acute rheumatic fever

Case:

A 9-year-old boy of Turkish descent acutely falls ill:

• Fever
• Arthritis of right knee, later of both knees
• Heart murmur
• High inflammation
  • ESR: 140 mm/hour
  • C-reactive protein: 160
    • Normally this is <3
• ECG: prolonged PR interval
• Echocardiography: mitral valve abnormalities

The diagnosis is acute rheumatic fever (ARF).

Clinical presentation:

ARF is an infection and an autoimmune reaction. It is a result of throat infection, but not of skin infection, by streptococcus pyogenes. Immunological effects of this bacteria are:

• Acute rheumatic fever
  • An autoimmune response
• Acute glomerulonephritis
  • A type III hypersensitivity reaction

Not the bacteria, but the immune response causes symptoms. ARF is a syndrome → a combination of symptoms and signs:

• Heart: carditis
• Joints: arthritis
• Neurological: chorea
• Skin: nodules and/or erythema marginatum

Epidemiology:

ARF mainly occurs in developing countries. Recurrent ARF may lead to rheumatic heart disease (RHD):

• Incidence of ARF: 0,5 million/year → 300.000 develop RHD
• Prevalence of RHD: 15 million
• Mortality of RHD: 233.000/year

ARF mainly occurs in children of young age, while RHD is more common among elderly. Approximately 3-6% of the population is susceptible.

Pathogenesis:

Pathogenesis is made up out of:

• Molecular mimicry: auto-immune hypersensitivity
  1. Type II reaction: initial damage → exposes self-antigens
     • IgG formed against streptococcus pyogenes reacts with an M-protein (and possibly group A carbohydrates) on the bacterium
       • M-proteins prevent opsonization
         • Have 3 parts: the response is directed against middle components which have rheumatoid epitopes
  2. The complex cross reacts with:
     • Myosin
     • Heart sarcolemma
     • Synovium
     • Articular cartilage
  3. Subsequent type IV response: Th1 cellular responses
     • The myocardium contains Aschoff bodies
• Genetic predisposition

The prognosis of the first episode is quite good → 27% has no abnormalities after 1 year. Therapy consists of:

• Anti-inflammatory drugs
• Slow-releasing penicillin: to prevent re-infection of streptococcus pyogenes

Jones criteria:

To diagnose ARF, the Jones criteria are used:

• 2 major or 1 major and 2 minor manifestations must be present, plus evidence of antecedent group A streptococcus infection
  • Chorea and indolent carditis do not require evidence of antecedent group A streptococcus infection
• Recurrent episodes require only 1 major or several minor manifestations, plus evidence of antecedent group A streptococcus infection

Therapy:

Therapy consists of anti-inflammatory drugs in the acute phase. This doesn’t have any effect on RHD.

Acute glomerulonephritis

Pathogenesis:

Acute glomerulonephritis is a type III hypersensitivity reaction, but not an autoimmune reaction. It almost has the same pathogenesis as ARF:

1. A streptococcus pyogenes antigen and an IgG antibody form an immune complex
2. The complement system is activated
3. The glomerulus becomes clogged → hypertension, edema and oliguria

Clinical image:

It is associated with certain M-types and can follow a skin or throat infection. Clinical features are:

• Oliguria
  • Very low amounts of urine
• Edema
• Hypertension

Usually, the prognosis is good. Microscopic images show hardly any nuclei, but if the complement system is activated, neutrophils and IgG-activated complements are visible.

Lues

Lues/syphilis flourished in Europe in the fifteenth century. For this reason, it is called the Romantic disease of philosophers, artists and politicians. It is not an autoimmune disease, even though it has the same symptoms.

Case:

A 58-year-old male is married and physically active, but has 20 pack years. His medical history shows:

• In the past 2 years
  • Urethritis
  • Eczema
• In the recent past
  • Edema and weight gain in the last 3 months
  • Eczema and erythema since 2 months

PCR on renal biopsy is negative for treponema pallidum. The diagnosis is lues.

Diagnosis:

Electromicroscopy shows electron-dense areas that are transmembranous (in the middle of the basal membrane). This membranous pattern is distinguishing for lupus nephritis, but in combination with the eczema and erythema also for syphilis/lues.

Pathophysiology:

Lues is a post-infectious glomerulonephritis of an infection with a gram-negative microorganism.

In case of renal involvement, immune complexes with treponema pallidum antigens and IgG antibodies are deposited in the kidney at the subepithelial position. Renal involvement is extremely rare and only occurs in 1% of patients with lues.

Treatment:

Penicillin is the treatment of choice for all stages. This is systemic treatment → renal involvement will resolve spontaneously.