[03.24] Autoimmune Diseases V2.pdf

The lack of response of our body to an antigen when it is presented or exposed to the lymphocytes

What is immunologic tolerance?

The ability of our immune system to recognize our own cell and choose not to react to it (unresponsive to its own antigens)

What is self-tolerance?

Normal cell metabolism, Viral infection, Intracellular bacterial infection

What are three ways self-antigens are generated by our own cells?

Central tolerance and Peripheral tolerance

What are the two groups mechanisms of tolerance can be classified into based on the site of immunoregulation?

Thymus

Where does central tolerance for T-cells occur?

Bone marrow

Where does central tolerance for B-cells occur?

Elsewhere, such as other tissues or in the bloodstream

Where does peripheral tolerance occur?

Negative selection or clonal deletion

What mechanism of central tolerance occurs for T-cells in the thymus?

Receptor editing and deletion

What mechanisms of central tolerance occur for B-cells in the bone marrow?

They may escape into the periphery

Why is central tolerance not a foolproof process?

Anergy

What is the term for T-cells being rendered unresponsive in peripheral tolerance when the antigen is presented without adequate levels of co-stimulators?

Apoptosis

What process results in the killing of self-reactive T-cells during negative selection in the thymus?

Autoimmune Regulator (AIRE)

What protein stimulates the expression of some peripheral tissue-restricted self-antigens in the thymus, critical for the deletion of immature T-cells specific for these antigens?

Regulatory T-cells

What do other T-cells that recognize self-antigens in the thymus develop into instead of dying?

Antigen receptor gene rearrangement

What is repeated during B-cell receptor editing, allowing new antigen receptors that are not specific for self-antigens to be made?

Apoptosis

What happens to self-reactive B-cells if receptor editing does not occur?

Anergy, Inhibitory receptors, Suppression, Apoptosis or deletion

What are the four mechanisms of peripheral tolerance?

Lack of co-stimulation or second signal

Why does T-cell action not occur completely even if they identify self-antigens in anergy?

CTLA-4 and PD-1

What are two examples of inhibitory receptors on T-cells, structurally homologous to CD28, also called checkpoint inhibitors or brakes of the immune system?

Tumor immunotherapy (e.g., lung cancer)

What area of treatment has utilized the development of antibodies that block CTLA-4, PD-1, and PD-L1?

Regulatory T-cells

What cells are responsible for the suppression mechanism of peripheral tolerance?

IL-10 and TGF-ß

What cytokines may regulatory T-cells secrete that inhibit lymphocyte activation and other effector functions?

Inheriting susceptibility genes and Environmental triggers (such as infections or tissue damage)

What are the two main combinations of factors from which autoimmunity arises?

Ankylosing spondylitis

What disease has the most striking association with a Human Leukocyte Antigen (HLA) gene, specifically the HLA-B27 allele?

HLA-B27 allele (Class I HLA allele)

Inheriting what allele increases an individual’s chance of developing ankylosing spondylitis by 100 to 200-fold?

Upregulate the expression of co-stimulators on antigen-presenting cells, and Molecular mimicry

What are the two proposed mechanisms linking infections and autoimmunity?

Breakdown of anergy or Activation of T-cells specific to the self-antigen

What are the two possible results if APCs presenting self-antigens upregulate co-stimulators due to infection?

Molecular mimicry

What mechanism involves microbes expressing antigens that share similar amino acid sequences with self-antigens, leading to activation of self-reactive lymphocytes?

Rheumatic heart disease

What is an example of molecular mimicry where antibodies against streptococcal proteins cross-react with myocardial proteins?

Epstein-Barr virus (EBV) and Human Immunodeficiency Virus (HIV)

What are two viruses that can cause polyclonal B-cell activation, potentially resulting in autoantibodies?

Release and structural modification of self-antigens, creating new antigens

What can tissue injuries common in infections do that activates T-cells?

Ultraviolet radiation (UV)

What is an environmental insult that can alter the display of tissue antigens?

Exposure of nuclear antigens

What does UV radiation-caused cell death lead to, which can elicit pathologic immune responses, as seen in lupus?

More common in women than in men

How is the gender bias in autoimmunity described?

Effects of various hormones and Currently unknown genes on the X-chromosome

What are two underlying mechanisms possibly involved in the strong gender bias towards autoimmunity?

Chronic, Sometimes with relapses and remissions, Damage is often progressive

What are three general features of autoimmune diseases?

Controlling the inflammation that is inappropriately directed against the body’s own tissues

On what does the management of autoimmune diseases rely?

Systemic Lupus Erythematosus (SLE)

What is considered the most well-known and well-studied autoimmune disease, often called the “Poster child” for autoimmune disease?

Production of autoantibodies (particularly antinuclear antibodies or ANAs)

What is the hallmark of SLE?

Anti-dsDNA (against double-stranded DNA) and Anti-Sm (against Smith antigens)

What two antibodies are diagnostic of SLE?

Forming immune complexes and Attacking their target cells

What are the two ways the pathogenic effects of autoantibodies in SLE occur?

Skin, Joints, Kidney, and Serosal membranes

What four organ systems are most prominently injured in SLE, though any organ can be affected?

Women in the reproductive age group (17-55 years old)

What demographic group does SLE predominantly affect?

Blacks and Hispanics

In which populations is the incidence of SLE 2- to 3-fold higher compared to Caucasians?

4

How many criteria must a patient classified as having SLE meet according to SLICC?

At least 1 clinical criterion and At least 1 immunologic criterion

What specific types of criteria must be included among the 4 criteria for SLE classification?

Indirect Immunofluorescence for ANA

What is the most widely used method to demonstrate the presence of antinuclear antibodies in SLE diagnosis?

The pattern of nuclear fluorescence

What suggests the type of antibody present in the patient's serum during indirect immunofluorescence?

Homogeneous, Rim/peripheral, Speckled, Nucleolar, Centromeric

What are the five patterns of nuclear fluorescence mentioned for indirect immunofluorescence for ANA, including the variation?

Antibodies to chromatin, histones, and double-stranded DNA

What do homogeneous patterns of nuclear staining reflect?

Antibodies to double-stranded DNA and sometimes to nuclear envelope proteins

What does the rim/peripheral pattern most often indicate?

Rim/peripheral

Which ANA pattern is commonly seen in SLE and is a variation of the homogeneous pattern?

Speckled

Which ANA pattern is the least specific because it is frequently observed?

Antibodies to RNA

What does the nucleolar pattern of fluorescence represent?

Systemic Sclerosis

In what disease are the Nucleolar and Centromeric patterns of ANA reported most often?

Antibodies specific for centromeres

What antibodies do patients with systemic sclerosis often contain, giving rise to the centromeric pattern?

Antiphospholipid Antibodies

What other type of autoantibodies, aside from ANAs, are present in almost 40% of Lupus patients, sometimes referred to as “Lupus anticoagulants”?

Hypercoagulable state (thrombosis, recurrent spontaneous miscarriages, focal cerebral or ocular ischemia)

What complications do patients with antiphospholipid antibodies face despite in vitro clotting delays?

Antiphospholipid Antibody Syndrome (APAS)

What is the condition involving autoantibodies against phospholipid binding proteins and related clotting complications?

Primary APAS

What term describes APAS developing without Lupus?

Secondary APAS

What term describes APAS developing in association with Lupus?

Any phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell

What is a Lupus Erythematosus (LE) Cell?

Homogeneous LE bodies or Hematoxylin bodies

What do nuclei of damaged cells become in vivo after reacting with ANAs and losing their chromatin pattern?

Failure of mechanisms that maintain self tolerance

What is the fundamental defect in SLE pathogenesis?

Genetic, immunologic, and environmental factors

What three categories of factors play a role in the failure of self tolerance in SLE?

Inherited deficiencies in complement proteins/components (C2, C4, C1q)

What genetic condition may impair the removal of circulating immune complexes, favoring tissue deposition in SLE?

Self-nucleic acids mimicking microbial counterparts

What can stimulate the production of pathogenic autoantibodies and induce inflammation in SLE via activation of Toll-like receptors (TLRs)?

Type I interferons

What is produced in SLE via activation of Toll-like receptors?

UV irradiation

What environmental factor may induce apoptosis and alter DNA to enhance recognition by TLRs, potentially exacerbating SLE?

Keratinocytes producing IL-1 (a cytokine promoting inflammation)

What is an immunologic effect of UV irradiation in SLE?

Hydralazine, Procainamide, D-penicillamine, Isoniazid

What are four drugs that can trigger an SLE-like response in humans?

Malar rash (butterfly rash)

What characteristic erythema along the bridge of the nose and cheeks is seen in half of all SLE patients?

Discoid rash

What skin lesion, similar to the malar rash but seen on the extremities and trunk, is characterized by varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy?

Vacuolar degeneration of the basal layer of the epidermis

What is seen microscopically in the involved areas of skin in SLE?

Perivascular inflammation in the dermis

What is another microscopic finding in the dermis of SLE skin lesions?

Deposition of immunoglobulin and complement (IgG deposits) along the dermo-epidermal junction

What does Immunofluorescence microscopy show in SLE skin lesions?

Glomerulonephritis and tubulointerstitial nephritis

What are two forms of clinically significant renal involvement common in SLE?

Deposition of immune complexes on the glomerular basement membrane

What causes Glomerular lesions in Lupus Nephritis?

Mesangium

Where are immune complexes first found in Class I: Minimal Mesangial Lupus Nephritis?

Less than 50%

What percentage of glomeruli are involved in Class III: Focal Lupus Nephritis?

Half or more

What percentage of glomeruli are affected in Class IV: Diffuse Lupus Nephritis?

Most frequent and severe pattern

How is Class IV: Diffuse Lupus Nephritis characterized?

Cellular crescents

What do epithelial cells produce in Class IV that fill the Bowman's space?

Subendothelial immune complex deposits

What causes circumferential thickening of the capillary wall, forming a wire loop structure in Class IV?

Diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes

What characterizes Class V: Membranous Lupus Nephritis?

Sclerosis of more than 90% of the glomeruli

What characterizes Class VI: Advanced Sclerosing Lupus Nephritis?

End-stage renal disease

What does Class VI: Advanced Sclerosing Lupus Nephritis represent?

Libman-Sacks Endocarditis (Nonbacterial verrucous endocarditis, valvular endocarditis, warty endocarditis)

What is the cardiac lesion seen in SLE, referring to warty deposits on the leaflets of any heart valve?

Chronic discoid lupus erythematosus, Subacute cutaneous lupus erythematosus, Drug-induced lupus erythematosus

What are three variants of SLE with prominent skin lesions?

Usually remains confined to the skin

What is the typical course of Chronic Discoid Lupus Erythematosus?

Antibodies to dsDNA are rarely present

What autoantibody finding is characteristic of Chronic Discoid Lupus Erythematosus?

Features intermediate between SLE and chronic discoid lupus erythematosus

How is Subacute Cutaneous Lupus Erythematosus described?

Skin rash that tends to be widespread, superficial, and generally non-scarring

What is the presentation of Subacute Cutaneous Lupus Erythematosus?

Strong association with antibodies with the SS-A antigen and with the HLA-DR3 genotype

What are two associations of Subacute Cutaneous Lupus Erythematosus?

Antibodies specific for histones

What autoantibodies are frequently seen in Drug-Induced Lupus Erythematosus?

HLA-DR4 allele

What allele puts people at greater risk of developing SLE-like syndrome after administration of hydralazine?

Rheumatoid arthritis (RA)

What chronic inflammatory disease affects joints and blood vessels and is triggered by autoantibodies specific for cyclic citrullinated peptides (CCPs)?

Anti-citrullinated peptide antibodies (ACPAs)

What are diagnostic markers that can be frequently detected in the serum of RA patients?

Rheumatoid factor (RF)

What is the collective term for IgM and IgA autoantibodies that bind to the Fc portion of IgG?

Sjögren Syndrome

What chronic disease results from an immunologically mediated destruction of lacrimal and salivary glands through lymphocytic infiltration and fibrosis?