What is an "Autoimmune Disorder"?

Updated: Apr 3, 2019


The Basics

  • Simply speaking, autoimmune disorders are when the host's inflammatory cells attack "normal/self" tissues causing damage to the host tissues.

  • Autoimmune disorders can occur as a result if B and T cells do not mature properly. Under usual circumstances, this occurs during a process called "tolerance" in which any T and B cells that respond to self-antigen would be either "re-trained" or "removed from duty".

  • Autoimmune disorders have genetic components, often related to HLA alleles, and can be triggered by environmental or infectious stimuli.

  • Women are more often affected than are males



Central vs. Peripheral Tolerance

B and T cells are first made in the bone marrow. During the process of maturation, these "baby"/immature Bs & Ts" must undergo a process of "Central" & "Peripheral" tolerance to prove that they will not cause harm to the host prior to being deemed "fit for duty" & released into the body.


B cells

  • B cells remain in the bone marrow for central tolerance: here, they are exposed to self-antigen. Remember- we don't want our soldier B cells to attack us, only the enemy

  • B cells that respond to self-antigen can either undergo receptor editing, in which they develop new receptors that do not react against self-antigen, or, they must die by apoptosis.

  • If a B cell is in the periphery (blood stream) and then reacts against a self-antigen, it enters an unresponsive state of anergy. It is thought the absence of co-stimulation by T cells renders B cells anergic.

T cells

  • T cells leave the bone marrow to undergo central tolerance in the thymus. Here is where they are exposed to self-antigen by antigen-presenting epithelial cells (APCs). If they are self- reactive, they can either choose to differentiate to become T regulatory cells, or, die via apoptosis.

  • Peripherally, T cells reactive to self-antigens may:

  1. Become anergic/non-reactive (particularly in the absence of co-stimulation)

  2. Be suppressed/inactivated by regulatory T cells

  3. Die by apoptosis.

  • Unfortunately, some self-reactive B and T cells end up in the circulation, where they cause chronic, often progressive, damage.

SYSTEMIC AUTOIMMUNE DISORDERS

Autoimmune disorders:

1. Rheumatoid arthritis

2. Systemic scerlosis (Scleroderma)

3. Sjogren Syndrome

4. Others (not discussed in this post): Systemic Lupus Erythematosus, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis


Bear in mind that autoimmunity can also be organ-specific, as in multiple sclerosis (damaging the white matter in the brain) or Type I diabetes mellitus (damaging beta islet cells producing insulin in the pancreas).



Rheumatoid arthritis


Tends to affect the synovial joints of the hands and feet early in the disorder.


Key mediators and their effects:

  • Helper T cells release interferon gamma (activates macrophages) and IL-17 (recruits inflammatory PMNs & monocytes). Activated T cells express RANKL, which promotes bone resorption.

  • Macrophages release tumor necrosis factor and IL-1 → Trigger the release of degradative proteases.

Characteristic damage of rheumatoid arthritis in a zoomed in view:


Inflammation of the synovium results in pannus formation (thickened synovial fluid with inflammatory cells, fibroblasts, and synovial cells that erode the cartilage).

  • Over time, the pannus on opposing bones forms a fibrous ankylosis, which may then become bony ankylosis.

  • These changes cause stiffness, swelling, and joint deformities.

  • Swan neck deformity: the proximal interphalangeal (PIP) joint is hyperextended and the distal interphalangeal (DIP) joint is flexed (thus, it looks like the neck of a swan).

Serum Markers:

  • Antibodies against citrullinated protein antigens (ACPAs), such as citrullinated fibrinogen, which is produced during inflammation.

  • Rheumatoid factor is also found in patients with rheumatoid arthritis; however, it's non-specific.


Systemic Sclerosis (aka Scleroderma)


Key mediators and their effects:

  • Scleroderma is a combination of autoimmunity, vascular damage, and fibrosis

  • Tumor growth factor Beta is a key mediator

Serum Markers:

  • Anti-centromere antibody (ACA)

  • Anti-Scl-70

Limited Systemic Sclerosis

Due to Anti-centromere antibodies- Affects the skin of the fingers, forearms, and face

visceral involvement, if any, occurs late.



CREST Syndrome (Limited SS)

  • Calcinosis,= calcified nodules form under the skin; they may progress to lesions.

  • Raynaud's phenomena = small vessels of the fingers and toes severely constrict in response to stress and/or cold. Initially, reduced blood flow turns the fingers white; as oxygen levels fall, the fingers appear bluish; and, finally, after blood flow is re-established, they become red.

  • Esophageal dysmotility = caused by collagen replacement of the muscularis layer of the esophagus; dysphagia and/or heart burn can result.

  • Sclerodactyly = hands take on a claw-like appearance because fibrosis of the dermis pulling the skin taught; dermal tightening can also occur in the face.

  • Telangiectasia =dilation of superficial micro-vessels; it commonly looks like a rash on the face or chest.

Diffuse Systemic Sclerosis

  • Manifests as widespread cutaneous fibrosis with quick progression to the viscera.

  • It is associated with Scl-70.

  • Examples of Organ Effects:

  1. Pulmonary fibrosis, in which the interstitial tissue becomes thick and fibrotic. Pulmonary fibrosis and hypertension are the leading causes of death from systemic sclerosis.

  2. Renal failure, due to systemic vascular damage and hypertension.

  3. Pericarditis and pericardial effusion.

  4. Damage to the villous structures in the small intestine, which leads to malabsorption.


Sjögren's Syndrome

  • Characterized by damage to the lacrimal and salivary glands mediated by interferons (types 1 & 2)

  • Autoantibodies (anti-SSA/Ro, anti-SSB/La), which are anti-nuclear autoantibodies (also in systemic lupus erythematosus)

Xerostsomia (aka “Dry Mouth”)

  • Destruction of salivary glands --> lead to ulcers and increased dental caries.

  • H&E of minor salivary glands: leukocyte infiltration that has damaged the tissues.

Keratoconjuctivitis sicca (aka “Dry Eye”)

  • Destruction of the lacrimal gland (located laterally above the eye) --> dec tear production

  • Thus, the eyes become dry, irritated, and more susceptible damage; vision may be impaired.

Other

  • Sjörgen's syndrome may have non-glandular effects, particularly in the joints, lungs, kidneys, and cardiovascular system.

Reference

These notes were adapted and modified from the awesome medical education website, DrawItToKnowIt.com. This is a GREAT website for visual learners. Please subscribe to their website to view the complete lecture and see step by step drawings and charts.


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Drawittoknowit.com "Autoimmune Disorders: Systemic" lecture. Accessed 3/21/19.


Autoimmune Image: Raid M. Al-Ani, University of Anbar. https://www.researchgate.net/post/What_are_the_autoimmune_diseases

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