Musculoskeltal System: Lec.2 - Autoimmune Diseases Of The Ms System

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Lecture Two:
Autoimmune Diseases of the Musculoskeletal System

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Autoimmune Diseases of the Musculoskeletal System

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2Q:

IMMUNOLOGIC TOLERANCE

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Refers to a state of unresponsiveness which is specific for a particular antigen. The most important form of this is "self-tolerance" to prevent autoimmune responses. There are several mechanisms for inducing or maintaining tolerance:
· Clonal deletion of self-reacting lymphocytes (e.g., thymic selection)
· Clonal anergy - the self-reactive clone is present but will not respond for some reason (e.g., lack of second signal)
· Suppression - inhibiting cellular activation or effector function, via interaction with suppressor cells or suppressive cytokines

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2Q:

Breakdown of tolerance may be due many unknown factors, which may include

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1) Inappropriate MHC expression
2) Failure of suppression mechanism(s)
3) Cross-reactivity and molecular mimicry

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2Q:

IMMUNOPATHOLOGIC MECHANISMS OF AUTOIMMUNE DISEASE

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1) T-cell activation leading to cytokine secretion with resultant cellular infiltration, vascular permeability and leakage, and inflammation, perhaps chronic inflammation
2) Autoreactive antibody - may be epiphenomena, directly pathogenic, or bind with antigen to form immune complexes. Used diagnostically
3) Excessive immune complex formation and deposition can result in complement
activation and subsequent inflammation, as seen in SLE, resulting in vasculitis, nephritis, necrosis, intense cellular infiltration, skin manifestations, or a combination of these.

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2Q:

Presentation of Systemic Lupus ERYTHEMATOSUS

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an autoimmune disease that
involves chronic, systemic inflammation. Multiple organ systems are usually involved and the disease affects females more than males by a 4:1 ratio, depending upon age of onset. The disease may have alternating remissions and exacerbations, and can be mild or deadly from renal failure, central nervous system involvement, or infections.

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2Q:

factors believed to contribute to or influence SLE:

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(a) Genetic susceptibility
(b) Hormonal factors
(c) HLA associations
(d) Autoantibodies
(e) Environmental factors

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2Q:

MAJOR IMMUNOLOGIC FEATURES OF SLE

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· Presence of anti-nuclear antibody (ANA), Antibody against double-stranded DNA
· Immune complexes deposit along glomerular basement membrane and at the dermal- epidermal junction
· Numerous other autoantibodies are present that react with platelets and erythrocytes

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2Q:

Reactive arthritis (Reiter’s Syndrome!) Presentation

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*STD (Chlamydia trachomatis (#1 cause), Salmonella, Shigella, Yersinia) or GI infection leads to inflammation of the jointzzz
-these organisms are getting into the joint spaces to trigger this autoimmune reaction.
the triad of arthritis, urethritis, and conjunctivitis, or commonly, arthritis with one of the other two. Reiter's usually affects males. The arthritis is recurrent or chronic, migratory, asymmetric and polyarticular, involving primarily joints of the lower extremity. Fever, malaise, and weight loss occur commonly with episodes of acute arthritis.

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2Q:

Reactive Arthritis is associated with what MHC component?

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There is association with HLA-B27 in 80% of cases.

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2Q:

What are Rheumatoid Factors? Where do they bind? How are they related to diseases?

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IgG, IgM, IgA react against, bind to Fc region of IgG (bind to other antibody)
-in diseases, start for form these autoreactive antibodies, the Abs particularly bind to the Fc region of IgG antibodies, so you get immune complexes formed, and this can activate compliment and lead to inflamm reactions in the joints themselves.

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2Q:

Citrullinated Peptides

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Some proteins in the body that undergo a post-translational modification where the arganine amino acids are changed to citrulline and some of those proteins are found in the joint spaces, and these pts. develop Abs against citrulline, and these APC Abs appear to be more specific for rheumatoid arthritis than rheumatoid factors, so they’re using more and more diagnostically to confirm a diagnosis of RA.

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2Q:

Rheumatoid arthritis associated helper T cells and HLA

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· Role of Th1 (produce IFN gamma) and Th17 (produce IL 17, a proinflamm mediator, recruit neutrophils) CD4+ T cells
· Inflammatory infiltrates of mononuclear and polymorphonuclear leukocytes in the joints
· 14 - 28% positive for ANA; Associated with HLA-DR4

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2Q:

Presentation of RA

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1. This disease characteristically begins in the small joints of the wrists, hands, ankles, knees, elbows, and shoulders and progresses in centripetal and symmetric fashion. Typically, the PIP and MCP joints are affected, but DIP joints are spared. Axial involvement, when it occurs, is limited to upper cervical spine; hip joint involvement is extremely uncommon.
2. About 25% of RA patients develop rheumatoid subcutaneous nodules, usually along the extensor surface of the forearm or other areas subjected to mechanical pressure. These are firm, oval or rounded masses up to 2 cm in diameter.
3. As RA is a systemic disease, a number of other structures/organs may be affected :
* acute necrotizing vasculitis of small or large arteries
* pleuritis or pericarditis
* damage to lung parenchyma by progressive interstitial fibrosis
**Proposed central role of TNF in controlling synovial inflammation in rheumatoid arthritis →activating inflamm rxns in the joint

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2Q:

DIAGNOSIS OF RHEUMATOID ARTHRITIS

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(need 4 of 7)
1. Morning stiffness
2. Arthritis of 3 or more joint areas
3. Arthritis of hand joints
4. Symmetric arthritis
5. Rheumatoid nodules (raised, firm over knuckles, elbows, ass’d with vasculitis)
6. Serum rheumatoid factor (RF)
7. Radiologic changes

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2Q:

Felty's syndrome

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association of rheumatoid arthritis, splenomegaly, and neutropenia. Felty's syndrome almost always develops in patients with high-titer rheumatoid factors and rheumatoid nodules, and HLA-DR4.

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2Q:

Myasthenia gravis features

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• Auto-antibody against acetylcholine receptors
• ~ 2 - 10/100,000 prevalence; all age groups
• Thymic abnormalities such as hyperplasia, thymoma

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2Q:

Process that leads to muscle weakness in MG

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In this disease, auto-reactive antibodies are formed against the acetycholine receptors at neuromuscular junctions. Immune complexes form, complement is activated, and the post-synaptic membrane is destroyed. This interference with normal nerve signals results in muscle weakness.

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Presentation of MG

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Muscle weakness and fatigability first become manifest in the muscles in most active use (e.g. the extraocular muscles and those in the face, tongue, and extremities).

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2Q:

CLINICAL PRESENTATION, DIAGNOSIS and TREATMENT OF MYASTHENIA GRAVIS

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There is wide variation in the clinical course of patients with earl y-onset MG. Muscle weakness and fatigability first become manifest in the muscles in most active use (e.g. the extraocular muscles and those in the face, tongue, and extremities).

Anticholinesterase drugs (pyridostigmine and neostigmine) are mainstay therapy.
Thymectomy is beneficial in the majority of cases (precise mechanism is unknown).
Plasmapheresis in combination with corticosteroids is also effective.

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2Q:

Juvenile rheumatoid arthritis (JRA)

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-people under 16 yrs
-involves large joints
-may present as Still's Disease
-spontaneous remission
-Cellular and humoral immune abnormalities
-high risk of chronic anterior uveitis.

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2Q:

Tx of JRA

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Patient management is directed at controlling inflammation so as to prevent permanent deformities with the simplest, safest, most conservative measures.

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2Q:

CRITERIA FOR DIAGNOSIS OF JUVENILE RHEUMATOID ARTHRITIS

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1. Age of onset < 16 years
2. Arthritis in 1 or more joints, defined as swelling or effusion, or the presence of 2 or more of the following signs: limitation of motion, tenderness or pain on motion, heat
3. Symptoms present for 6 weeks or longer
4. Type of onset during the first 6 months classified as:
a) Polyarthritis - 5 joints or more
b) Oligoarthritis (pauci-articular arthritis) - 4 joints or fewer
c) Systemic disease - arthritis with intermittent fever
5. Exclusion of other forms of juvenile arthritis

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2Q:

Polymyositis/Dermatomyositis Immunologic Features

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* Anti-nuclear antibodies (ANA) and auto-antibody against cytoplasmic antigens
* Lymphocyte and plasma cell infiltration of involved muscle
* Production of a cytotoxic lymphokine
* Focal deposition of immune complexes and complement in involved tissues

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2Q:

Most common category of polymyositis/dermatomyositis

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"skeletal muscle that is damaged by a lymphocytic inflammatory process"

Muscle weakness can begin insidiously in the proximal muscles of the upper and lower extremities. In dermatomyositis, you have the presence of skin lesions as well, with a subtle rash over the eyelids (heliotrope rash) and knuckles(Gottron’s sign), or over large areas of the body.

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2Q:

IMMUNOPATHOGENESIS in Polymyositis/Dermatomyositis

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There is demonstrated lymphocytic and plasma cell infiltration of affected muscle.
Inappropriate recognition of some muscle antigen could lead to lymphocyte activation and subsequent cytokine production. Various auto-antibodies are produced. Corticosteroids are the treatment of choice.

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2Q:

Diagnosis of Polymyositis/Dermatomyositis

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At least 3 of the following criteria must be present for a definitive diagnosis:
1) Proximal muscle weakness (shoulder or pelvic area)→getting out of chair, walking up stairs, keeping head up, but the facial muscles are spared.
2) Biopsy evidence of myositis
3) Elevated muscle enzymes in the blood (glutamic-oxaloacetic transaminase, creatine phosphokinase, and aldolase)
4) Electromyographic findings of myopathy
***10-20% of the pts will have cancer of some kind

tx is corticosteroids

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2Q:

Ankylosing spondylitis

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**The finding of HLA-B27 on tissue typing contributed to the diagnosis of ankylosing spondylitis.
-Chronic inflammatory disease of the sacroiliac joints, vertebrae, entheses
-Lower back pain + anterior uveitis (reddening of the eyes)
-HLA-B27+
-Young men 15 – 35 years old
-X-ray, Schober’s test

starts with sacroiliac joints, ascend up the vertebrae, stiffening of the spine.

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2Q:

TNF's role in inflammation

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Tumor Necrosis Factor Alpha is a very potent mediator of inflammation within the joint spaces, probably involved in activating inflammatory reactions within the joint.
- induces production of proinflammatory cytokines (Il-1, Il-6, chemokines)
-stimulates cells within join to break down the matrix which surrounds them
-stimulates and activates endothelial cells, leading to further recruitment of cells within the joint
-stimulates macrophages to produce matrix metallo-proteinases and free radicals
*target TNF for drug therapies!

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2Q:

ANAs

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Diseases tend to make abnormal Abs, that react to nuclear antigens, and they tend to have characteristic patterns, associating with certain CT diseases, and not others as much. So they are helpful somewhat in the clues of the dx of the disease.
General patterns of ANAs that are found include a homogeneous pattern where the Abs stain in a diffuse way the entire nucleus

Peripheral pattern- stain primarily the nuclear membrane
Speckled pattern-
Nucleolar pattern-
Only one not seen routinely in SLE the nucleolar one.
*in RA, 14-28% positive for ANA