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Yr 2 - Clinical Pathology > Autoimmune Diseases > Flashcards

Autoimmune Diseases Flashcards

1
Q

What cells are involved in innate immunity? What about in adaptive immunity?

A

Innate:

  • Macrophages
  • Dendritic cells
  • Mast cells
  • Neutrophils
  • Complement

Adaptive:

  • T cells
  • B cells
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2
Q

What is involved in innate immunity?

A
  • Inflammation in target tissues
  • No learning going on - no memory
  • Cells recognise antigen (pattern recognition receptors)
  • No amplification
  • Little regulation
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3
Q

What is speed of response of innate immunity? Duration?

A

Speed - fast response (hours - days)

Duration - short duration

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4
Q

What is involved in adaptive immune response?

A
  • Learned response in immune organs
  • Highly specific (T and B cells receptors)
    • Against a specific bacteria/virus etc (not broad classes of antigens like innate immunity) that cells have encountered in the past
  • Strong memory and amplification component
  • Many regulatory mechanisms
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5
Q

What is speed of response of adaptive immunity? Duration?

A
  • Speed: slow response (days to weeks for initial exposure)
  • Responses may last months - years
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6
Q

Are the innate and adaptive immune systems completely separate?

A

No - lots of crossover

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7
Q

What do innate immune cells detect/attack?

A

Directly detect and attack antigenic targets (e.g. microbes) at sites of infection e.g. barrier organs (skin, gut)

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8
Q

What mechanisms are involved in innate immunity?

A
  • Phagocytosis
  • Cytotoxicity (e.g. complement sticks to cell walls of microbes)
  • Inflammatory mediators and chemokines to attract other cells
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9
Q

How are inflammatory mediators released by the innate immune system involved in crosstalk with the adaptive immune system?

A

Inflammatory mediators and chemokines attract T cells/B cells

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10
Q

How are dendritic cells involved in crosstalk with the adaptive immune system?

A

Dendritic cells are APCs –> digest antigen and present it to T cells (via MHC II)

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11
Q

What is the result of dendritic cells presenting antigen to T cells and B cells? Where does this occur?

A
  • Immune memory to determine specific learned responses
  • Occurs in lymphoid tissues
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12
Q

How can B cells and T cells then interact with the innate immune system? What do T cells active? What do B cells activate?

A

Adaptive immune cells activate innate immune cells, directing tissue inflammation to specific targets

  • T cell cytokines activate monocytes, macrophages
  • B cell antibodies activate complement
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13
Q

What are the 5 main components of innate immune system inflammation?

A
  1. Phagocytic cells
  2. Histamine-producing cells
  3. Complement
  4. Cytokines
  5. Chemokines
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14
Q

What are 3 examples of phagocytic cells? Functions?

A
  • Neutrophils: eat and destroy pathogens
  • Macrophages: also produce chemokines to attract other immune cells
  • Dendritic cells: also present antigen to adaptive immune system
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15
Q

Which phagocytic cells also produces chemokines to attract other immune cells?

A

Macrophages

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16
Q

What are examples of APCs?

A

dendritic cells, macrophages, Langerhans cells and B cells.

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17
Q

What are examples of histamine producing cells?

A

Mast cells, basophils, eosinophils: produce histamine and other chemokines and cytokines

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18
Q

What is effect of histamine?

A

Vasodilatation, attract other immue cells

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19
Q

What are histamine-producing cells involved in?

A
  • Defence against parasites
  • Wound healing
  • BUT causes allergy and anaphylaxis
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20
Q

What is the complement system?

A

A part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen’s cell membrane.

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21
Q

How can the complement system be activated by the adaptive immune system?

A

Via antibodies

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22
Q

Cytokines vs chemokines?

A

Cytokine is a general term used for all signalling molecules - signalling between different immune cells (e.g. innate to adaptive, adaptive to innate).

Chemokines are specific cytokines that functions by attracting cells to sites of infection/inflammation.

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23
Q

APC goes to lymph node and presents antigen to Th cell. What change does Th cell then undergo? What is net result?

A
  • Th cell then differentiates from a naive Th cell to a Th1 cell

OR

  • Th cell then differentiates from a naive Th cell to a Th2 cell

Net result –> inflammation

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24
Q

What cytokines does Th1 cell release?

A

Inflammatory cytokines:

  • IL-2
  • IL-12
  • IFN-y
  • TNF-a
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25
Q

What do Th2 cells then interact with? What do they release?

A
  • Release IL-4, IL-5, IL-6, IL-10
  • Crosstalk with B cells –> turns B cells into memory B cells –> plasma cells (these produce antibodies and autoantibodies)
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26
Q

What is autoimmunity? What are the main characteristics?

A

The adaptive immune system recognises and targets the body’s own molecules, cells and tissues (instead of infectious agents and malignant cells).

  • T cells that recognise self antigens
  • B cells and plasma cells that make autoantibodies
  • Inflammation in target cells, tissues and organs is secondary to actions of T cells, B cells and autoantibodies
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27
Q

What is autoinflammation? What are the main characteristics? How is it different from autoimmunity?

A
  • seemingly spontaneous attacks of systemic inflammation
  • no demonstrable source of infection as precipitating cause
  • absence of high-titre autoantibodies and antigen specific autoreactive T cells
  • No evidence of auto-antigenic exposure
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28
Q

Autoinflammation vs autoimmunity:

  1. Innate or adaptive?
  2. Main cellular involvement?
  3. Antibody involvement?
  4. Clinical features?
  5. Conceptual understanding?
  6. Main genetic susceptibility?
  7. Therapy?
  8. Examples?
A

Autoimmunity:

  1. Adaptive immunity
  2. B and T cells
  3. Autoantibodies present
  4. Continuous progression
  5. Breaking of self-tolerance
  6. MHC class II associations and adaptive response genes
  7. Anti-B and T cells
  8. Monogenic ALPS and IPEX, Polygenic RA and SLE

Autoinflammation:

  1. Innate immunity
  2. Neutrophils, macrophages
  3. Few or no autoantibodies
  4. Recurrent, often seemingly unprovoked attacks
  5. Tissue-specific factors/danger signals
  6. Cytokine and bacterial sensing pathways
  7. Anti-cytokine (IL-1, TNF, IL-6)
  8. Monogenic hereditary periodic fevers, polygenic Crohn’s disease, spondylarthropathies
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29
Q

Autoimmunity vs autoimmune disease?

A

Autoimmunity is present in all individuals; however, autoimmune disease occurs only in those individuals in whom the breakdown of one or more of the basic mechanisms regulating immune tolerance results in self-reactivity that can cause tissue damage.

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30
Q

How is tolerance involved in autoimmunity?

A
  • T cell selection in thymus and B cell selection in bone marrow
    • ​Normally autoimmune ones are destroyed and ones that aren’t autoimmune are positively selected
    • Failure of this ‘tolerance’ in autoimmunity
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31
Q

How is genetic predisposition involved in autoimmunity?

A
  • Certain HLA (MHC) types select for certain self-antigens
  • Other genes that regulate immune functions
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32
Q

How are antigenic factors involved in autoimmunity?

A
  • Infections that trigger autoimmune responses
  • Environmental triggers: UV light, smoking
  • Alterations in self-proteins that increase their immunogenicity
33
Q

Combination of factors of autoimmune diseases:

A
  1. Genes
    1. Born with genes but not with disease
  2. Immune regulation
    1. The immune system has many regulatory functions to shut down immune functions – tolerance of self is a dynamic state
  3. Environment
    1. Not born with disease - must be environmental triggers
34
Q

What is tolerance?

A

Tolerance is the prevention of an immune response against a particular antigen. The immune system is generally tolerant of self-antigens, so it does not usually attack the body’s own cells, tissues, and organs.

35
Q

Where does T-cell central tolerance occur? Peripheral?

A

Central: Thymus

Peripheral: spleen, lymph nodes

36
Q

Explain central-T cell selection in thymus

A
  • As T cells are randomly generated in the thymus, they are tested against self antigens
    • If they react to self antigens –> deletion
    • Inbetween (e.g. recognises self antigen weakly) –> turned into a regulatory T cell
      • Tregs control the immune response to self and foreign antigens and help prevent autoimmune disease.
    • If doesn’t react –> positive selection
  • Positively selected T cells move out to the periphery
37
Q

What genes are MHC class I and II encoded by?

A

HLA genes

38
Q

Where is MHC I found? What is it recognised by?

A
  • Found on all nucleated cells
  • Presents antigen to CD8+ T cells (cytotoxic)
39
Q

Where is MHC II found? What is it recognised by?

A
  • Found on dedicated APCs
  • Presents antigen to CD4+ T helper cells (Th1 or Th2)
40
Q

What is the only way in which T cells can recognise antigens?

A

Is presented to them either via MHC I or II

41
Q

How can class II MHC genes predispose to autoimmunity?

A

MHC type that presents a particular autoantigen a bit better –> susceptibility

42
Q

What are the other causative associations with autoimmunity?

A
  • Sex (hormonal influence)
    • Women >> men
  • Age
    • Autoimmunity more common in elderly
  • Sequestered (hidden away) Antigens
    • May be recognised as foreign by the immune system (e.g. cell nucleus, eye, testis)
  • Environmental triggers
    • Infection
    • Trauma-tissue damage
    • Smoking
43
Q

What is molecular mimicry?

A

the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides.

44
Q

How is molecular mimicry seen in rheumatic fever?

A

Antibodies against M protein of Streptococcus also react against the glycoproteins of the heart

45
Q

What is citrulline? What is result of citrullination of proteins? What disease is this important in?

A
  • Citrulline is an amino acid (not encoded in genome as not used to make protein)
  • Citrullination is the conversion of the amino acid arginine in a protein into the amino acid citrulline (post translational)
  • Citrullination of proteins make them look more foreign –> makes them more immunogenic
    • ​Important in rheumatoid arthritis
46
Q

What can failure to clear apoptotic debris lead to? What disease is this seen in?

A

Increases the availability of sequestered antigens inside the cell –> higher chance of autoimmunity eg. systemic lupus erythamatosus

47
Q

What is a typical organ specific autoimmune disease?

A

Autoimmune thyroid disease

48
Q

What is organ specific autoimmunity?

A
  • Affect a single organ
  • Autoimmunity restricted to autoantigens of that organ
  • Overlap with other organ specific diseases
49
Q

What is systemic autoimmunity?

A
  • Affect several organs simultaneously
  • Autoimmunity associated with autoantigens found in most cells of body
  • Overlap with other non-organ specific diseases
50
Q

What diseases are typical of systemic autoimmunity?

A

Connective tissue diseases

51
Q

Case 1

History

A 28-year-old woman with recent tiredness and difficulty concentrating had experienced a decline in memory over the last several months. She also noted decreased frequency of bowel movements and an increased tendency to gain weight. She felt chilled without light sweater, even in warm weather.

Examination

She was 5’5” tall and weighed 125 lb. Her pulse rate was 58 beats per minute and her blood pressure was 138/88. She had a slightly puffy face and her eyebrows were sparse, especially at the lateral margins. The deep tendon reflexes were normally contractive, but showed delayed relaxation.

What is disease?

A

Hypothyroidism

52
Q

What autoimmune disease can lead to hypothyroidism?

A

Hashimotos thyroiditis

53
Q

How does Hashimotos thyroiditis lead to hypothyroidism?

A
  • Destruction of thyroid follicles by autoimmune process
  • Associated with autoantibodies to thyroglobulin and to thyroid peroxidase​
    • CD4 T cell recognise antigens found in thyroid
    • Autoreactive B cells and CD8 T cells
54
Q

Case 2

History

30 yrs old women presents with anxiety, weight loss, diarrhea and palpitations. Although it is winter she hardly notices cold weather. She finds it almost impossible to sleep but despite this she seems to have abundance of energy.

Examination

She had swollen red eyes, rapid pulse and sweaty hands. She has rapid reflexes.

What is the disease?

A

Hyperthyroidism

55
Q

What autoimmune disease can cause hyperthyroidism?

A

Grave’s disease

56
Q

How can Grave’s disease lead to hyperthyroidism?

A

Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody –> leads to hyperthyrodism

Autoantibody binds to TSH receptor on thyroid cell –> overactive

57
Q

Case 3

History

58 yrs old man presents with difficulty keeping his eyes open, speaking and swallowing. His family have noticed he hardly smiles any more. He finds that his problems are worse as the day progresses.

What is disease?

A

Myasthenia gravis

58
Q

How is Myasthenia gravis caused?

A

Autoantibodies block the ACh receptor –> error in the transmission of nerve impulses to muscles.

59
Q

What is Myasthenia gravis?

A

A long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, trouble talking, and trouble walking

60
Q

Case 4

History

A Caucasian woman of 61 yrs has had increasing fatigue for 3 months, and tingling in her feet for 2 weeks. She has vitiligo and FH of hypothyrodism.

  • Hb very low
  • WBCs and platelets quite low
  • Mean cell volume very high

What is disease?

A

pernicious anemia

61
Q

What is MCV test?

A

Mean corpuscular volume. There are three main types of corpuscles (blood cells) in your blood–red blood cells, white blood cells, and platelets. An MCV blood test measures the average size of your red blood cells, also known as erythrocytes.

62
Q

MCV in pernicious anaemia?

A

The MCV is higher than normal when red blood cells are larger than normal. This is called macrocytic anemia. Macrocytic anemia can be caused by: Vitamin B-12 deficiency. Pernicious anemia is a type of macrocytic anemia due to the body not being able to absorb vitamin B-12.

63
Q

Who is most prone to macrocytic anaemia?

A

Elderly, vegans, and alcoholics

64
Q

MCV in iron deficiency anaemia?

A

Low (microcytic anaemia)

65
Q

How can MCV determine type of anaemia?

A

Low –> iron deficiency (microcytic)

High –> B12 deficiency (macrocytic)

66
Q

What is needed for the absorption of B12?

A

Intrinsic factor

67
Q

What is intrinsic factor produced by? How are these cells targeted in autoimmune?

A

Parietal cells in stomach - autoantibody can target this cell so no intrinsic factor and no B12 absorption

68
Q

How can pernicious anaemia be treated?

A

B12 injection

69
Q

Symptoms of SLE?

A
  • Butterfly rash on face (photosensitive malar rash)
  • Hair loss
  • Joint pain (and swelling)
  • Severe fatigue
  • Headaches
  • Anaemia
  • Mouth ulcers
    • Roof of mouth
70
Q

How can SLE manifest as pleural effusion?

A

SLE causes inflammation on lining of lungs –> causes fluid build up around lungs –> patient breathless

71
Q

What does SLE stand for?

A

Systemic Lupus Erythematosus

72
Q

Mechanism of SLE?

A
  • Antinuclear antibodies –> i.e. antibodies form against many different molecules in the cell nucleus:
    • ddDNA
    • dsDNA
    • Ribosomes
    • Histones
  • Nuclear self-antigens are normally always intracellular, so shielded from the immune system – sequestered antigens
  • In cell death by apoptosis nuclear material is digested and cleared
  • In cell death by necrosis nuclear antigens may not be cleared and may then act as antigens to the immune system
    • ​Some people have genetic defects in mechanisms to clear cell debris
73
Q

Why is the sun bad for lupus patients?

A

Many people with lupus experience photosensitivity or unusual sensitivity to sunlight. This can trigger symptoms such as skin rashes, itching, and burning. Excess sun exposure can also cause flares in systemic lupus, triggering symptoms such as joint pain, weakness, and fatigue.

In people with lupus, the cells are much more sensitive to the damage caused by UV radiation –> UV light causes DNA damage, and cell death

74
Q

How are immune complexes involved in some autoimmune diseases?

A
  • Antibodies against the antigens in the nucleus combine with their targets to form IMMUNE COMPLEXES in the circulation
  • Immune complexes deposit in any organ (e.g. kidney) – activate complement and cause inflammation
75
Q

Type II vs type III hypersensitivity reactions?

A
  • Type II –> involve IgG and IgM antibodies directed against cellular antigens
  • Type III –> involve the interactions of IgG, IgM, and, occasionally, IgA1 antibodies with solube antigens to form immune complexes.
76
Q

How can immune complex deposition lead to renal failure (lupus nephritis)?

A
  1. Immune complex deposition
  2. Inflammation
  3. Leaky glomerulus
  4. Loss of renal function
  5. Scarring (now it is irreversible)
  6. Irreversible renal failure
77
Q

Examples of overlapping ‘connective tissue’ diseases?

A
  • Systemic lupus erythematosus
  • Scleroderma
  • Polymyositis
  • Sjogrens syndrome
  • Ubiquitous antigens (components of the cell nucleus) cause multisystem inflammation
78
Q

Which infection can lead to rheumatic fever?

A

Infection with group A strep (S. pyogenes); bacterial sore throat or scarlet fever

Yr 2 - Clinical Pathology (80 decks)

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