Immunology - Type III Hypersensitivity (Lupus Eythematosus)

Question 1

Mechanism

Answer 1

the IgG antibodies are typically specific for DNA and nucleoproteins both of which are part of own cells making them self-reactive, with lupus a DNA autoantigen may get released from a damaged cell where a circulating self-B cell might find it and bind to it, if a T helper cell that is also specific for the same DNA autoantigen is close by it will help activate the B cell and enable it to differentiate into an IgG secreting machine specific to that DNA autoantigen, the antibodies are trying to bind a small soluble antigen and there may be a lot of antigen relative to the number of antibodies (small antigen-antibody complexes are less immunogenic (less attractive to the macrophages) and they don’t get removed from the bloodstream as quickly), -> the immune complexes float around in the blood longer and typically make their way into the basement membrane layer of various blood vessels (ionically attached to or deposited in) -> complement system (family of 9 small proteins (C1 - C9) that work in an enzymatic cascade to clear infections) C1 binds the antibody-antigen complex -> chain reaction activates C2 through C9 -> fragments C3a + C4a + C5a are anaphylatoxins (increase vascular permeability = edema) + act as chemokines (recruit other cells like neutrophils to the site that try and phagocytize the immune complex but usually can’t -> degranulate during this process, they degranulate (lysosomal enzymes and reactive oxygen species which cause inflammation and tissue necrosis which ultimately causes vasculitis or inflammation of the blood vessels) -> inflammation = further cellular destruction, and more autoantigen release, repeating the cycle again

Question 2

Tolerance

Answer 2

Normally your body should only react to things that are foreign or not-self, maintained by tolerance where only non-self-reactive B and T cells are allowed to mature, whereas self-reactive B and T cells aren’t, some self-reactive cells escape and these can mount an immune response against autoantigens or self-antigens

Question 3

Most commonly in areas…

Answer 3

like the kidney where the blood is being filtered (glomerulonephritis) as well as the joints since blood plasma is being filtered to produce synovial fluid (inflammation of the joints (arthritis))

Question 4

Definition

Answer 4

severe, relapsing, remitting multisystem autoimmune disease, onset can occur at any age however it most typically presents in young adult females (female:male 9:1)

Question 5

Juvenile onset SLE

Answer 5

JSLE, childhood form of SLE, relatively rare condition with an unclear prevalence in the UK, onset occurs prior to the age of 18 (typically between 12−16), accounts for up to 20% of all cases of SLE.

Question 6

Statistics

Answer 6

the annual incidence of juvenile SLE is estimated to be 0.36–0.9 per 100 000 children per year, generally higher in non-Caucasian children (especially black, Hispanic, and Asian populations)

Question 7

Diagnosis

Answer 7

based upon the revised American College of Rheumatology classification criteria for adult onset SLE, 11 criteria (which include malar rash, oral or nasal ulceration, nephritis and a positive test for nuclear antibodies) of which four have to be met simultaneously or periodically

Question 8

immunopathogenesis

Answer 8

interplay between genetic and environmental factors resulting in activation of all components of both the innate and acquired immune system

Question 9

Immune system dysfunction

Answer 9

production of autoantibodies against autoantigens, inflammation and organ damage,
increased apoptosis and defective clearance of apoptotic material, autoantigens cluster in surface blebs of apoptotic cells increasing their immune-exposure, saturation of physiological processes to safely remove apoptotic debris amplifies autoantigen exposure

Question 10

Antinuclear antibodies

Answer 10

presence of antinuclear antibodies has been detected in the serum of a majority of patients before the onset of clinical disease symptoms, levels of certain auto-antibodies have been found to correlate with disease activity supporting a role for these antibodies in mediating disease pathology, antibodies form antibody-nuclear antigen immune complexes which deposit in tissues and trigger local inflammation

Question 11

Neutrophils in SLE

Answer 11

the most abundant leukocytes in human blood, one of the first immune subsets to respond to a microbial insult, in SLE dysregulation in both their function and cell death, increased formation and decreased dismantling of Neutrophil Extracellular Traps (NETs) = source of autoantigen exposure granulocyte gene signature which may relate to the presence of an inflammatory subset of neutrophils (low density granulocytes)

Question 12

Innate immune system involvement

Answer 12

• a majority of patients with SLE display an increased expression of type I Interferon (IFN)–regulated genes (IFN signature)
• Plasmacytoid dendritic cells (pDC) are the main producers of Type I IFN’s in response to viral infections, in SLE these cells are also induced to synthesize IFN via Toll-like receptor (TLR) ligation by endogenous derived nucleic acids, a source of which may be increased apoptosis and NETs
• Type I IFN contributes to loss of tolerance and activation of autoreactive T and B cells with production of autoantibodies

Question 13

B cell involvement

Answer 13

cells of the immune system that make antibodies, inappropriate activation and proliferation of autoreactive memory B cells in the periphery

Question 14

T cell involvement

Answer 14

T cells that are reactive with several nuclear autoantigens have been isolated from the peripheral blood of SLE patients, T cells from SLE patients also display abnormal signalling and secrete cytokines that promote inflammation, regulatory T cells (cells important in maintaining cell tolerance) have been shown to be low in SLE and their suppressive function impaired