HC30: Pathology of autoimmunity

Autoimmune diseases and hypersensitivity

Hypersensitivity reactions and autoimmune diseases correlate with each other:

• Hypersensitivity reactions
  • Mechanisms show that the immune system overreacts to certain stimuli
  • Are present in many autoimmune diseases
    • Type I hypersensitivity forms an exception
• Autoimmune diseases
  • Have a hypersensitivity reaction as part of their pathogenesis

Autoimmunity and infection

Patients with a variety of auto-immune diseases report that an infectious disease seems to precede the development of their auto-immune disease. In these cases, an infection can be:

• A trigger
  • For the production of antibodies that cross-react with autoantigens
• An enhancer
  • For activating the immune system by activating inflammatory cells
• A second, third of fourth hit in a complex pathogenesis

Examples are:

• Many patients with IgA nephropathy report flu-like episodes with gastrointestinal and upper airway involvement before the occurrence of hematuria
• Patients with ANCA-associated vasculitis often report that their initial symptoms consisted of upper airway disease with sinusitis

Koch’s postulates:

The association of specific microorganisms with diseases came about as a consequence of the work of the German physician Robert Koch. He formulated a set of criteria that could be used to identify the pathogen responsible for a specific disease. These criteria came to be known as Koch’s postulates:

• The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms
• It must be possible to identify microorganism from a diseased organism
• The microorganism should then cause disease upon introduction into a healthy organism
• The microorganism should be identified as being identical to the original specific causative agent
• If detection of the microorganism predates disease and/or if its quantity correlated with disease severity a causal relationship becomes more likely

In case of autoimmunity, the microorganism is replaced by a factor such as an antibody. The criteria are a little less strict than for infectious diseases → for instance, the factor must be present in most organisms.

ANCA-associated vasculitis:

Anti-neutrophil cytoplasmic autoantibodies (ANCA) pass these criteria. The antibodies are directed against components in granules of neutrophils, for example against proteinase-3, myeloperoxidase and elastase. Most patients with systemic vasculitis have high values of these antibodies, while healthy patients hardly have any of them.

Other immune mediated diseases are:

• Rheumatoid arthritis
• Sjögren’s disease
• Systemic sclerosis
• Idiopathic interstitial fibrosis of the lung

In some patients, antibodies can be present long before they have symptoms or the disease is diagnosed.

Rheumatoid Arthritis

Rheumatoid Arthritis is a systemic, chronic inflammatory disease, affecting many tissues but principally the joints → hand-knuckles start to swell. A typical patient is a 40-year-old woman. It is relatively frequent in the population, but there are many treatment options.

Histology:

Histological images show a proliferating synovitis that frequently destroys the cartilage or bone, with disabling arthritis. There are villous projections of granulation tissue with inflammatory infiltrate and proliferation of synovial lining → a pannus. Many mononuclear cells and plasma cells are present.

Extra-articular manifestations:

Rheumatoid arthritis may appear in virtually any organ → extra-articular manifestations. A peculiar manifestation is the rheumatoid nodule, for example in the skin or lung. In this case, a necrotizing granuloma with palisading histiocytes is visible.

An infectious origin like tuberculosis has the same symptoms. It must always be excluded because the required treatment is completely different → immunosuppression would lead to growth of the mycobacterium tuberculosis.

Rheumatoid Factor:

The Rheumatoid Factor (RF) plays an important part in cases of rheumatoid arthritis. RF is an IgM antibody that binds to the Fc fragment of IgG → forms an immune complex. 80% of rheumatoid arthritis patients have RF, while up to 20% of the healthy population have RF. However, RF is also visible in other autoimmune diseases such as SLE.

Sjögren’s disease

Sjögren’s disease is a chronic disease characterized by immunologically mediated destruction of the lacrimal and salivary glands. This leads to a dry mouth and dry eyes. It was first described by Henrik Sjögren, a Swedish ophthalmologist.

The typical patient is a woman of 35-45 years old. Serology may be positive for:

• Sjögren’s syndrome-A (SS-A)
• Sjögren’s syndrome-B (SS-B) RF

Treatment is symptomatic. Immunosuppression is only applied in case of multi-organ involvement. It is important to be aware of Sjögren’s Syndrome in relation to SLE or rheumatoid arthritis.

Diagnostics:

The diagnostic work-up of Sjögren’s disease includes Schirmer’s test → production of tears is measured by attaching papers to the eyes:

1. Normal: >15 mm wetting of the paper after 5 minutes
2. Mild: 14-9 mm wetting of the paper after 5 minutes
3. Moderate: 8-4 mm wetting of the paper after 5 minutes
4. Severe: <4 mm wetting of the paper after 5 minutes

Histology:

Histology of a salivary gland biopsy shows a T-cell infiltrate, mixed with plasma cells that secrete antibodies locally. The T-cells destroy the glands.

Greenspan grades the severity of the disease according to the number of foci with inflammatory cells including lymphocytes and plasma cells.

Systemic sclerosis

Systemic sclerosis is a chronic disease of unknown etiology, characterized by abnormal accumulation of fibrous tissue in the skin and multiple organs. It possibly is T-cell mediated. There are 2 types of systemic sclerosis:

• Diffuse scleroderma: may involve skin, GI tract, kidneys, lungs, heart, skeletal muscles
• Limited scleroderma: mild skin involvement

In some cases, the abnormal build-up of fibrous tissue in the skin can cause the skin to tighten so severely that the fingers curl and lose their mobility. The typical patient is a woman of 50-60 years old.

Symptoms:

Systemic sclerosis has multiple symptoms:

• Skin problems
  • Raynaud phenomenon: purple/blue, cold fingers
  • Collagenization of the skin
  • Stiffness
• Esophagus problems
  • Difficulty in swallowing
  • Malabsorption
• Other organs involved
  • Heart
  • Kidney
  • Lung

Histology:

Histology shows a hypocellular dermis and fibroblasts producing collagen. The epidermis is narrow and rigid. It is mostly characterized by an absence of inflammation. There is a huge atrophic process that removes glands and normal structures from the skin.

Typical patients

Auto-immune patients are mainly women. This may be caused by hormones or pregnancy. When a woman is pregnant, her immune system changes → the body needs to accept the baby → women have a flexible immune system.

There is a 2-route way in which cells from the mother enter the fetus and vice versa. In some cases, immune cells of the fetus are found in women 30 years after giving birth. This also is the case the other way around → immune cells of mothers can be found in children. Most of these cells are found in the lungs and spleen, while less are found in the brain and thymus.