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Immunology > Autoimmune disease 14/02/23 > Flashcards

Autoimmune disease 14/02/23 Flashcards

1
Q

What is autoimmunity?

A

Immune response of auto antibodies against self antigens. Humoral or cell mediated immune response against the components of the own cells/tissues.

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2
Q

What are auto antibodies?

A

Altered cell (auto antigen) elicits the production of antibodies.

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3
Q

What are auto or self antigens?

A

Antigens present in one’s own cells. Altered by the action of bacteria, viruses, chemicals, or drugs.

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4
Q

What is an autoimmune disease?

A

Autoimmune diseases is a group of disorders in which tissue injury is caused by humoral (by auto-antibodies) or cell mediated immune response (by auto-reactive T cells) to self-antigens.

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5
Q

What happens in autoimmune disease?

A

The immune system attacks self-cells. This attack can be directed either against a very specific tissue or to a large number of tissues.

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6
Q

What are the types of immune responses involved in autoimmune diseases?

A

-Adaptive immune response
-Highly specific pathogen-medicated process
-B-cells (humoral immunity) and T cells (cellular immunity)
-Distinguish between self and non self
-Develop immune repertoire ‘immunological memory’

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7
Q

What are the four causes of autoimmune disease?

A

Sequestered or hidden antigens:
-Antigen in the secluded places and not accessible to the immune system

Neo antigens:
-Altered or modified antigens by physical (irradiation), chemical (drugs), or microbial agents (intracellular viruses)

Molecular mimicry:
-A foreign antigen resembles self
-Many species share organ specific antigens

Loss of immunoregulation:
-Loss of self-tolerance causes by the over activity or lowered activity of T and B cells

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8
Q

What are examples of endocrine autoimmune diseases?

A

Type 1 diabetes - autoantibody target is pancreatic B cells
Grave’s disease - autoantibody target is thyroid proteins and cell antigens
Hashimoto’s thyroiditis - autoantibody target is thyroid proteins and cell antigens

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9
Q

What is the endocrine?

A

Endocrine glands contain specialised cells that are common targets for organ specific autoimmunity because they express tissue-specific proteins and have a very goof blood supply.

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10
Q

What is type 1 diabetes?

A

Selective destruction of insulin-producing β-cells in the
pancreas:

-Autoantibodies target insulin, glutamic acid decarboxylase and specific β-cell proteins
-CD8+ T cells mediate cell destruction

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11
Q

What is Grave’s disease?

A

-Hyperthyroidism and over production of thyroid hormones which cause the thyroid to be enlarged
-Exophthalmos
-Heat intolerance and anxiety
-Bacterial/viral trigger
-Abs to Thyroid Stimulating Hormone Receptor (TSHr)

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12
Q

What is the pathology and treatment of Grave’s disease?

A

Increased levels of:
-T3 (triiodothyronine)
-T4 (thyroxine)
-Persistent TSHr stimulation

Decreased levels of:
-TRH/TSH

Treatment:
-Thyroidectomy
-Anti-thyroid drugs (carbimazole)
-Radioiodine-131

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13
Q

What is Hasimoto’s disease?

A

-Hypothyroidism
-Thyroid gland enlargement (goitre)
-Reduced thyroid function (hypothyroidism)
-Abs to thyroid oxidase – Cytotoxicity
-Reduced metabolic rate

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14
Q

What is the pathology and treatment of Hasimoto’s disease?

A

Increased levels of:
-TSH

Decreased levels of:
-T3 & T4

Treatment:
-Replacement therapy (Lthyroxine/Liothyronine)
-Natural desiccated thyroid (NDT)

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15
Q

What are examples of neurological autoimmune diseases?

A

Myasthenia Gravis - autoantibody target is acetylcholine receptor
Lambert-Eaton syndrome - autoantibody voltage-gated calcium ion channels

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16
Q

What is Myasthenia Gravis?

A

-Skeletal muscle weakness – worsens with activity
-Symptoms subside after periods of rest
-Antibodies to the AChR & MuSK (Muscle-Specific Kinase)
-Facial muscles affected (Speech/vision)

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17
Q

What is Lambert-Eaton syndrome?

A

-Antibodies to the voltage-gated Ca2+ channels
-Decreases Ca2+ influx into nerve terminal
-Proximal & distal muscle weakness (Legs > arms)
-Ataxia

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18
Q

What are examples of blood autoimmune diseases?

A

-Haemolytic anaemia - autoantibody target is IgG/IgM bind to RBCs
-Thrombocytopenic purpura - autoantibody target is platelet glycoproteins

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19
Q

What is haemolytic anaemia?

A

-Organ specific autoimmune disorder in which IgG
and IgM autoantibodies bind to RBCs and activate
complement
-RBCs become spherocytic and are phagocytosed by
macrophages
-Symptoms of fatigue

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20
Q

What is thrombocytopenic purpura?

A

-Low platelet count
-Antibodies (IgG) to platelet surface glycoproteins
-Bleeding, bruising, rash (pupuric)
-Haematomas – mucous membranes

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21
Q

What are examples of skin autoimmune diseases?

A

Vitiligo - autoantibody target is tyrosinase
Pemphigus vulgaris - autoantibody target is desmoglein

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22
Q

What are three features of systemic autoimmune diseases?

A

IgG auto-antibodies formed against cellular components can cause systemic autoimmune disease:
-Extracellular matrix proteins (collagen)
-Cell surface proteins (HLA antigens)
-Cytoplasmic proteins (actin, myelin)
-Nuclear components (histone proteins, DNA)

Systemic autoimmune diseases often involve periods of intense inflammation followed by periods of
relative calm (remissions):
-Lupus (SLE), Multiple sclerosis, Rheumatoid arthritis
-Ectopic lymphoid tissues form in MS & rheumatoid arthritis

Immune complexes (e.g. Rheumatoid factors) form when IgM, IgG and IgA autoantibodies bind to the Fc region of human IgG:
- Immune complexes accumulate in many tissue

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23
Q

What are the five examples of systemic autoimmune diseases?

A

Poly/Dermatomyositis - autoantibody target is nuclear, DNA, tRNA, synthetases
Rheumatoid arthritis - autoantibody target is proteins and complexes
Multiple sclerosis - autoantibody target is myelin sheath
Systemic lupus erythematosus - autoantibody target is DNA, nuclear proteins, and complexes
Sjogren’s syndrome - autoantibody target is nuclear protein and complexes

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24
Q

What is dermatomyositis?

A

-Profound muscle weakness (symmetrical)
-Rare: 6-7 out of 100,000
-Perifascicular atrophy (occurrence of small muscle fibers at the periphery of a fascicle)
-Proximal muscles
-T-cell infiltration into muscle
-Skin involvement
- Heliotrope rash
- Gottrons papules

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25
Q

What is rheumatoid arthritis?

A

-RA is a systemic autoimmune disorder that usually affects the joints of wrists, hands, elbows, shoulders, knees and ankles symmetrically
-In RA the synovial membranes (synovium) of the joints become inflamed and produce excess fluid which accumulates in the joint
-Cartilage becomes rough and pitted and bones often become eroded

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26
Q

What is multiple sclerosis?

A

-Destruction of the myelin sheath
-Brain and spinal cord lesions
-Sensory disturbances
-Muscle control
-Visual disturbance
-Relapse/remittance/secondary

27
Q

What is systemic lupus erthematosus?

A

-Wide-range of symptoms and affected organs
-Nuclear antibodies (Chromatin) – ANA (Anti-nuclear
antibodies)
-Misdiagnosed (mimic)
-Patients experience fatigue, pain (muscle/joint), weakness
-Unpredictable in nature

28
Q

What is Sjogren’s syndrome?

A

-Dry mouth and eye – primary symptom
-Immune cells target glands
-May impact multiple organ systems muscles/kidney/lungs
-Varied severity

29
Q

What are the mechanisms of self antigens?

A

Antigens are molecules or molecular fragments that can be bound by an MHC molecule and presented to a T-cell receptor

-An autoantigen is a self-antigen (an antigenic component/amino acid sequence) of the body that can provoke an immune response by the individual’s
own immune system
-Inappropriate autoimmune responses to self-antigens can involve:
-humoral mechanisms via B-cells and antibodies
-cell-mediated mechanisms via T-cells and cytokines

30
Q

What are the mechanisms of T cells?

A

-T cells are diverse in function
-Interaction with MHC antigen complex often dictates fate as to which T cell it will clonal expand into, for example, helper T cell, memory T cell, suppressor T cell, cytotoxic T cell.

31
Q

What are the mechanisms of B cells?

A

Produce antibodies in response to infection.

32
Q

What is the process of a B cell becoming a plasma cell?

A
  1. Antibodies on B cell surface recognise and attach to antigen, which is processed internally and a fragment of the antigen is combined with HLA class II.
  2. HLA class II antigen fragment complex is displayed o B cell surface.
  3. Receptor on T helper cell recognises HLA complex and cytokines are produced by the helper T cell to activate B cells.
  4. B cell us activated by cytokines and begins clonal expansion. Some of these B cells become plasma cells which produce antibodies against that specific antigen.
33
Q

What is the mechanism of clonal selection?

A
  1. Antigens bind to receptor on a specific B lymphocyte.
  2. The B lymphocytes proliferate to form a clone.
  3. Clones then become plasma cells and memory B cells.
  4. Plasma cells and memory B cells can then be used for the adaptive immunity to produce antibodies and remember antigens a long time after initial infections with the antigen. Clonal selection is a clonal expansion of immune cells in response to infection.
34
Q

What is tolerance?

A

-The ability to ‘tolerate self-antigens’ results from exposure of ‘self-antigens’ to autologous (self) lymphocytes in early development
-Tolerance is fundamental to the success of the immune system
-Failure to tolerate self-antigens in the presence of other factors can trigger the development of an autoimmune disease

35
Q

What is central tolerance?

A

-Regulation of B- & T-cells proliferating in the thymus & bone marrow renders them un-reactive to self-antigen
-During early maturation B & T cells are sensitive to self-antigen but regulatory processes nullify this response

36
Q

How does central tolerance eliminate T cells?

A

T-cell receptor (TCR) gene rearrangements in immature T-cells randomly generate thousands of antigen specific TCRs, therefore, T-cells that express auto-reactive TCR’s need to be eliminated.

The thymus selects and eliminates auto-reactive T-cells if:
-it is very active in early life (located near the heart)
-it positively selects T-cells with TCRs that bind to antigen associated with MHC expressed by epithelial thymocytes
-it negatively selects, and induces apoptosis in T-cells with high avidity (binding) for self-antigens on epithelial thymocytes
-thymus macrophages phagocytose apoptotic (dead) T-cells

37
Q

What is positive and negative selection in central tolerance?

A

In bone marrow there is the proliferation of thymocytes. They generate a large repertoire of T cell receptors. Then both positive and negative selection occurs.
Positive selection - retain useful thymocytes
Negative selection - eliminate dangerous thymocytes

Thymic cortical epithelial cells rich in MHC molecules (present antigens for the T cells). T-cell must be able to recognise/bind MHC. Around 98% of thymocytes die during selection steps due to being auto reactive. Around 2% enter circulation and some will still be autoreactive.

38
Q

How do T cells develop in the thymus?

A

-Immature thymocytes start in the subcapsular region of the thymus.
-They are then exposed to different cortical epithelial cells to check their response.
-If they pass they move to the cortico-medullary junction which has dendritic cells which also test the thymocytes.
-If they pass these checks then they move into the medulla of the thymus and are tested with macrophages and medullary epithelial cells and if they pass they become mature T cells.

39
Q

How does T cell central tolerance occur in autoimmune diseases?

A

Autoimmune T-cells can be activated in a pathogen-specific or a non-specific manner by infection:

Specific - specific pathogen antigens are presented to T-cells via T-cell receptor-MHC interactions.
Non-specific - by inflammation or reduced regulation by cytokines.

Inappropriate class II MHC expression activates B- or cytotoxic T-cells in:
-pancreatic b-cells express high levels of class II MHC in diabetes
-thyroid cells express high levels of class II MHC in Grave’s disease

Viruses promote Interferon-g release by T-cells which can increase class II MHC expression by cells that should not express it, this may help induce an autoimmune disease following a viral infection.

40
Q

How does central tolerance eliminate B cells?

A

Thousands of B cell clones are randomly generated by gene rearrangements during
foetal development, many will be autoreactive and need eliminating by tolerance. Developing B-cells undergo positive and negative selection in bone marrow and germinal centres of other lymphoid tissues. Most auto-reactive cells undergo apoptosis but some survive.

41
Q

How does B cell central tolerance occur in autoimmune diseases?

A

When autoreactive B-cells are stimulated by an auto-antigen they migrate to the T cell area of
secondary lymphoid tissues:
-if T-cell help is not available the B cells fail to thrive and die
-if they receive T-cell help they may survive and cause disease

  • Some viruses (Epstein-Barr virus, Cytomegalovirus) and bacteria can induce non-specific polyclonal B-cell activation. Activated B-cells can produce IgM which may combine with IgG to form immune complexes.
42
Q

What is AIRE?

A

AIRE is a regulatory element (Autoimmune Regulator (AIRE)). AIRE promotes the ectopic transcriptional activity of a large number of chromosomal locations, thereby enhancing the
expression by medullary epithelial cells (MECs) of genes that would normally only be expressed in specific tissues. This ‘shadow’ of the peripheral self in MECs is then presented to immature thymocytes, either directly by the MECs themselves, or indirectly by uptake of antigens released from MECs by thymic dendritic cells (DCs). Differentiating T cells that recognize these antigens are
then removed primarily by apoptotic clonal deletion, although some may survive by adopting alternative fates that have regulatory rather than autoreactive properties. These mechanisms thus prevent the autoimmune attack of peripheral organs. There is a clear match between the antigens that are ectopically expressed under the dictates of Aire and the specific antigenic targets that
manifest in its absence.

43
Q

What is an example of how AIRE can cause an autoimmune disease?

A

Example - Autoimmune Polyendocrinopathy Syndrome Type I

  • Dysfunction of multiple endocrine glands
  • Stems from mutations in AIRE gene
  • Loss of tolerance
  • Persistent fungal infections (mucosal)
  • Affects parathyroid and adrenal gland
44
Q

What is the regulatory element FOXp3?

A

Regulatory T cell (master regulator)

-Transcriptional regulator
-Development and function
-Commitment to Treg phenotype from precursor cells

45
Q

What is the regulatory element Tregs?

A

Regulatory T-cell

-Express CD4/CD25 & FoxP3
-FoxP3 – crucial in immune suppression
-Mutations in FoxP3 gene – disease (IPEX)
-Suppress activation, proliferation & cytokine production in CD4+/CD8+ T cell

46
Q

What is peripheral tolerance?

A

B and T cells that survive elimination by central tolerance and make there way into the peripheral. Peripheral tolerance ensures they are eliminated.

47
Q

How does peripheral tolerance occur by anergy?

A

Induction of anergy:
Example - If dendritic cells are not appropriately activated and present self-antigen to T cells without signals 2 and 3 (co-stimulation and cytokine signals), they will produce T cells that are tolerant or anergic to that self-antigen.

-Inactivation of T-cell following encounter with antigen
-Lack of co-stimulatory molecules (HLA-B7)
-Anergic cells may undergo apoptosis

48
Q

How does peripheral tolerance occur by suppression?

A

-T-Regs suppress T-cell activity
-Inhibitory cytokines (IL-10, TGF-β)
-CTLA-4

49
Q

How does peripheral tolerance occur by regulation?

A

Deletion of autoreactive T cells via apoptosis. Development of “induced” regulatory T cells (Tregs). T cells exposed to the cytokine TGF-beta can differentiate into “induced” T regulatory cells in the peripheral tissues. “Induced” T regulatory cells have similar effector functions as natural T regulatory cells, but they are produced in the periphery rather than in the thymus.

-HLA-B7 co-stimulator on APC membrane
-Regulation by CTLA-4
-Co-stimulation downregulates T-cell function

50
Q

What is sequestered antigen exposure?

A

Antigens hidden in ‘privileged sites’ can’t participate in tolerance. Privileged sites such as thyroid colloid, testes, myelin, in cells (histones & DNA). Privileged sites have
restricted / limited access for T-cells.

51
Q

What are examples of sequestered antigen exposure?

A

-Sperm antigens avoid early tolerance processes because sperm do not develop until
puberty, antigen released during a vasectomy can cause auto-Ab formation.

-Eye trauma in one eye can cause sympathetic ophthalmia (both eyes)

-Auto-antibodies to type IV collagen in Goodpasture’s syndrome causes glomerulonephritis (kidney) in all patients. Patients who smoke can also develop
pulmonary problems because auto-antibodies can enter damaged lung tissue.

52
Q

What is molecular mimicry?

A

Several viruses and bacteria possess antigenic peptide sequences (determinants) that are identical or similar to host-cell components:

-Klebsiella pneumonia nitrogenase SRQTDREDE
-HLA-B27 molecule KAQTDREDL
-Potential cause of ankylosing spondylitis long-term condition in which the spine and
other areas of the body become inflamed)

53
Q

How are autoimmune diseases transferred?

A

-Through pregnancy. This is through transplacental antibody transfer.

-Through genetics. Several family members can have the same autoimmune disease due to inheritance. HLA is the dominant genetic factor that affects susceptibility.

54
Q

What are risk factors for the development of an autoimmune disease?

A

-Hypersensitivity reactions
-Failure to tolerate self-antigens involving mechanisms such as sequestered antigen, molecular mimicry, MHC-II expression
-Bacterial or viral infections
-Non-specific activation of T-cells and B-cells
-Genetic susceptibility (inherited factors)
-Endocrine factors (female predominance)
-Adverse reactions to drugs
-Ageing (immunosenescence)
-Environment (UV exposure)
-Hormonal risks

55
Q

Why can hormones be a risk factor for autoimmune diseases?

A

Most autoimmune disease are more common in women exceptions for diabetes, male infertility, and ankylosing spondylitis.

Female sex hormones have a role in autoimmune diseases susceptibility but
the mechanisms are not understood. Oestrogens inhibit cytotoxic/regulatory T cells
enabling T cells to be activated and help B cells to release antibody. Androgens may have a protective effect.

56
Q

Why can drugs be a risk factor for autoimmune diseases?

A

Some prescription drugs also appear to induce autoimmune disease:

-15-20% taking procainamide (anti-arythmia drug), and 7-13% taking hydralazine (vasodilator) develop drug induced Lupus
-drugs may cross-react or conjugate with host tissues
-drugs may reduce tolerance or sensitise immune cells
-drugs may effect macrophage antigen processing

57
Q

Why can age related factors be a risk factor for autoimmune diseases?

A

In young people 1% of the T-cell population is replaced each day but this reduces with age. As the body ages the size of the thymus declines by 90% (involution):

~ by the age of 50 new T-cell production has declined by 20%
~ by the age of 70 new T-cell production has almost stopped

Senescence of the remaining T-cell clones contributes to autoimmunity because existing T-cell clones expand as the thymus fails to develop new T cells and the frequency of autoimmunity increase. Stress, poor diet, lack of exercise, lack of sleep, abuse of alcohol and tobacco may affect the immune system and increase autoimmune risk.

58
Q

What are the treatments of autoimmune diseases?

A

Current therapies are not cures, the aim is to reduce symptoms and severity using drugs. Immuno-suppressant drugs are widely used:

~ corticosteroids (prednisolone)~ azathioprine
~ methotrexate ~ chlorambucil
~ cyclophosphamide ~ cyclosporin A

  • Corticosteroids are the strongest drugs available for reducing inflammation,
    however, they have serious side effects at high doses, their use may worsen infection resistance, high blood pressure, heart failure, diabetes, peptic ulcers, and osteoporosis
  • A major problem with immuno-suppressants is that patients become vulnerable to infections and cancer
59
Q

What is DMARDs?

A

Disease-modifying anti-rheumatic drugs
-Target the disease and not the symptoms
-Biological and conventional forms of DMARD

60
Q

What causes disease in pemphigus foliaceus?

A

Antibodies against EC5 appear before symptomatic pemphigus foliaceus. These antibodies do not bind cell surface desmoglein and do not cause disease. However, intramolecular epitope spreading occurs and antibodies against EC1 and EC2 are formed. These autoantibodies cause disease.

61
Q

What is intermolecular epitope spreading?

A

Intermolecular epitope spreading is the gradual expanding of antibody responses to include autoantigens derived from many different cellular constituents.

62
Q

Why does rheumatic fever occur after strep throat?

A

Rheumatic fever arises when cross-reactive antibodies made against S. pyogenes bind to epitopes on human heart, joint, and kidney tissue, causing inflammation. In serious cases, heart failure can result.

63
Q

What infections are associated with autoimmune diseases?

A

Group A Streptococcus
Rheumatic fever

Chlamydia trachomatis
HLA-B27
Reiter’s syndrome

Shigella flexneri
HLA-B27
Reactive arthritis

Borrelia burgdorferi
HLA-DR2, DR4
Lyme disease

Coxsackie A
HLA-DQ2, HLA-DQ8 DR4
Type 1 diabetes

Immunology (10 decks)

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