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Principles Of Pathology > Diseases of immunity > Flashcards

Diseases of immunity Flashcards

1
Q

What is immunity split into?

A

Adaptive immunity= lymphocytes, T and B cells,

Innate immunity= First defence, macrophages, mucosal barriers, skin, etc

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2
Q

Explain in general how lymphocytes are made?

A

T cells start in the thymus as haematopoietic stem cells. From there they either become positive or negative or double positive. (CD4+) Those that are to negative become T reg cells. They they go to the CMJ to be escorted into seocondary lymphoid organs, spleen, peyers patch etc.

B cells, start in the bone marrow. Starts off as a pro- B cell going to pre- B cell. The VDJ chains convert it to an immature B cell where the B cell is released into the periphary. To a mature B cell either a memory or plasma cell

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3
Q

What is thymic involution and what can it lead to?

A

The thymus anatomically is largest when early and young. During puberty it starts involution. However, the thymic output of T cells does not shut down just the environment around it becomes “less”. As a result it causes immunosenescence. Which explains why old people’s immunity is not as good.

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4
Q

What is the alpha/beta TCR lineage?

A

This is what T cells need to become commited to. TCR delta genes are located within the alpha gene cluster, so these need to be removed. The process of deletion creates a (sjTREC) by product.

Therefore, measurement of the (sjTREC) product is a good marker for thymic output. They have been shown to decline with age. Different dog breeds have also undercome variance in (sjTREC) values showing some dogs are more susceptible in other dogs.

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5
Q

How is tolerance and auto immunity made?

A

Following screening for positive selection, and eradication of MHC unreactive T cells, they are subject screened against self peptides. Under the control of the autoimmune regulator (AIRE). If this is comprimised then the species will be subject to many auto immune diseases. Most of these therefore will go through clonal deletion.

However, those that do not exhibit as much negativity are recruited as natural fucntional T regulatory cells. Rather than undergoing apoptosis they express the foxp3 gene. preventing the t cell of releasing pro inflammatory cytokines and releasing instead regulatory/immunosuppresive cytokines like IL-10.

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6
Q

How are pathogens detected in presence of an infection?

A

Through pattern recognition receptors (PRRs) that function to detect molecules that are intrinsically foreign.

They are expressed in the extracellular fluid, on the plasma membrane, inside intracellular vesicles or in the cytoplasm.

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7
Q

How are viruses detected?

A

Viruses are hard to detect but most detections are due to the virus signalling the body that there is an infection through the use of their nucleic acid. Toll like receptors and cytoplasmic helicase communicates that there is a virus infection taking place. Signalling via these pathways will trigger other molecules like NF-kb that migrate into the nucleus, binding to specific promoter elements. In particular interferon type 1.

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8
Q

What does activation of type 1 interferon mean?

A

It means that there will be a classical cytokine receptor response with JAK-STAT. With the transcription factors binding to the interferon stimulated response element, within the promoters of key virus resistance genes.

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9
Q

What are the PRR’s that detect bacterial infection?

A
  1. C type lectins- Detect foreign carbohydrates, rich in mannose sugars.
  2. Toll like receptors (TLRs)- vaious TLR’s recognise different bacterial points, like TLR4 which detects flagellum.
  3. NOD-like receptors, which are expressed in the cytoplasm. Recognise larger breakdown molecules from PAMPs.
  4. Soluble PRRs include component C3. C reactive protein function to bind to microbes in extracellular fluid.
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10
Q

Why are macrophages important in immunity?

A

They express a multitude of PRRs and use their detection to trigger responses whether it be phagocyotsis, anti-microbial defenses or the production of pro-inflammatory cytokines. Dendritic cells use their PRR’s to engage with T cells in the lymph node.

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11
Q

Why are danger signals good for the adaptive immune system?

A

Causes the adaptive immune system to react appropriately to antigenic stimulation. PRR stimulation leads to the upregulation of CD80 and CD86, the key co-stimulatory molecules required for CD28 ligation. The profile of PRR stimulation can alter the cytokine output from the presenting cell, thus intiating t cell differentiation in the lymph node.

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12
Q

What are the possible outcomes of different cytokine responses?

A

https://s3.amazonaws.com/brainscape-prod/system/cm/173/509/301/a_image_thumb.png?1450818409

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13
Q

What do vaccine adjuvants do?

A

They can be used to influence the response to the antigenic component by targeting particular PRRs and generating the necessary signals to drive the immune response. ie. fashioning a particular Th response

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14
Q

What diseases are GSD’s susceptible to?

A
  • Inflammatory bowel disease (IBD)
  • Anal furunculosis
  • systemic aspergillosis
  • deep pyoderma
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15
Q

What are the two different type of Anal furunculosis and their meanings?

A

Fistulous- All the way through the colon

Ulcerative- only on the epidermis side of things

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16
Q

Is it an immunodeficiency disease?

A

No, it is an immune mediated disease, as discovered of late.

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17
Q

How are bacteria controlled in the GIT?

A

Macrophages recognise by PRRs, send signal to paneth cells which send anti microbial peptides.

Usually illiciting a TH3 cell which releases an IgA response.

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18
Q

So why is anal furunculosis different in response to a normal bacteria?

A

INNATE: Due to PRR’s being mutated. As a result there is increased invasion or antigenic exposure of microbe. Leading to increased secretion and permeability.

ADAPTIVE: Type IV hypersensitivity to microbial infection. So from an anti-inflammatory to a pro inflammatory environment.

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19
Q

Why are some lesions ulcerative in anal furunculosis therefore?

A

Usually the PRR’s go to the M2 macrophage and Th3 response to generate a mucosal immunity/tolerance. However, in some there the PRR’s trigger a M1 macrophage and Th1 response which triggers inflammationa and tissue destruction. Instead of the tolerance and this is mainly due to defective PRR’s triggering the M1 macrophage and cascading from there.

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20
Q

What are the underlying causes of AF and IBD?

A
  • Increased intestinal permeability.
  • IgA deficiency
  • Inappropriate IgE response to harmless antigen.
  • Poor T regulatory cell responses.
  • Defective innate immune responses to bacteria.

Ciclosporin deals with the immune mediated inflammatory response but not the underlying disease.

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21
Q

Why are GSD’s more prone and susceptible to IBD and AF then?

A
  • Selective IgA deficiency in this breed in particular
  • Seems to be a defective PRR (TLR4/TLR5/NOD2)
  • Which is also associated with Crohns disease.
22
Q

What are the important immune response genes?..in both innate and adaptive immunity?

A

Innate:

  • Toll like receptors
  • NRAMP1
  • Cytokine genes

Adaptive:

  • MHC
  • CTLA4
  • Cytokine genes.
23
Q

How does a cell recognise specific anchor residues when only one MHC molecule can accomodate one antigenic peptide?

A

By expressing multiple MHC molecules each with a different peptide binding groove. Thus, enabling presentation of different sets of peptides.

24
Q

How many MHC class molecules do humans have and how many varients?

A

Two lots of 3 variants.

MHC class 1 has 3 different types (A, B & C) whilst

MHC class 2 has 3 different types (DR, DP, & DQ)

Humans are heterozygous therefore express 6 different polymorphic genes.

25
Q
A
26
Q

What happens when there is a lack of MHC diversity in some gene pools?

A
  1. Infection: small gene pool, can lead to widespread susceptibility, to infectious disease in the population. Not enough diversity in the peptide binding capability,
  2. Vaccination: MHC genes influence presentation of vaccine antigen (particularly when sub-unit vaccines are used). Some animals might fail to respond appropriately and are not protected when they subsequently encounter the pathogen.
  3. Certain MHC molecules are associated with hyperactive immune responses and increased risk of autoimmune disease.
27
Q

What have some species become extinct?

A

Due to the lack of diversity in the MHC gene pool, leading to a lower defence system against wider range of diseases.

28
Q

What dog breed to more susceptible to parvovirus and why?

A

Rottweilers have shown to have an increase risk in parvovirus due to studies illustrating only 3 diffferent MHC types. Meaning their gene pool is low.

29
Q

How do autoimmune diseases link to MHC genes?

A

MHC molecules can fundamentally target self and cause destruction in some cases. (type1a diabetes is a classic example of the pancreatic beta cells doing this).

30
Q

What is CTLA4 and why is it important in autoimmune diseases?

A

Cytotoxic T cell lymphocyte antigen 4 has said to have different nucleotide polymorphisms (SNPs) which influence the CTLA4 that is produced. Which of course means different that if the soluble form is produced CTLA4 (exon 3 deletion) then it could explain why there is T cell dysfunction and less immunity. Which ties back in with immunogenetics and MHC class promoters.

31
Q

What is hypothyroidism and what is produced as a bystander effect?

A

Lymphocytic thyroiditis leading to thyroid atrophy. Clear evidence for an immune-mediated process of tissue destruction in the endocrine gland.

The bystander production is usually Thyroglobulin autoantibodies (TGAA), these are likely mediated by pathogenic T cells.

Therefore a TGAA elisa can confirm this.

32
Q

What is hypoadrenocorticism?

A

Lymphocytic adrenalitis leading to adrenalcorticol atrophy. Tissue destruction in the endocrine gland. present with glucocorticoid and mineralcorticoid deficiency. Diagnosis by ACTH stimulation test- flat line cortisol response.

Prognosis:

High chance of addisonian dogs developing hypothyroidism later in life. Genetic association with DLA and CTLA4 genes.

33
Q

What diabetes do canines have?

A

TYPE 1. THEY CAN NEVER HAVE TYPE 2. A large dog , like really large will not develop type 2 ever. Has to be from genetic.

34
Q

What turns T cells on?

A

https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/479/a_image_thumb.png?1450975528

35
Q

What turns B cells on?

A

https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/517/a_image_thumb.png?1450975556

36
Q

How are T cells tolerance made? i.e. positivity and negativity?

A

https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/518/a_image_thumb.png?1450975653

37
Q

What is peripharal tolerance and can you draw the intrisic and extrinsic main properties?

A

Central tolerance is imperfect intrisically and extrinsically so the periphary will deal with these imperfections.

https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/528/a_image_thumb.png?1450975748

38
Q

What is this showing?

https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/567/q_image_thumb.png?1450976608

A

T reg blocking the normal function of this cell. Which indirectly blocks the normal cell signalling the inflammtory cell to the response site. As a result this is indirect.

39
Q

What are Treg cells?

A

They are the key component to peripheral immune tolerance. The regulate/ suppress or kill, convential T/B cells, neutrophils, NK cells, NKT cells, and even osteoclasts.

Various subsets of T regs cells, however CD4+ CD25 high express FoxP3 gene.

FoxP3 allows genes to autoimmune suppresion rather than self attack, allows for self tolerance as a result.

40
Q

What are the molecular interactions in activation of T cells?

A
  1. MHC, APC expressing MHC, interacting with a TCR, with the APC antigen.
  2. co-stimulatory receptors- interaction with a co stimulatory molecule. Which are around the TCR molecule most times. I.e. not a CD4+ T cell but a co stimulatory molecule like CD28 and B7
  3. Cytokines ligate, and help a T cell response.

All fully commited for a full T cell response.

41
Q

What is this showing? https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/681/q_image_thumb.png?1450976702

A

MHC class I binding peptides, stimulating CD8 cells. In the absence of APC’s in vitro, and directly block the effects of the cytokines released. So the CD8+ directly blocked the MHC cells.

42
Q

Why is CTLA4 important in Tregs and bring it back to how this can have an effect on different breeds?

A

Able to stimulate a dendritic cell and block its main function of releasing pro inflammatory mediators. In particular releasing Foxo3 which inhibits IL-6 an inflammatory mediator. And also stopping tryptophan phosphoralating into kynurenin a key T cell growth factor. Going back to the breeds in soluble CTLA4 those with to much of it or being soluble able to pass into the bloodstream could have an autoimmune response to other cells. Which is seen in diabetes.

https://s3.amazonaws.com/brainscape-prod/system/cm/173/605/752/a_image_thumb.png?1450976941

43
Q

What are the three main tolerances in the periphary?

A
  • T cells
  • Deletion and ignorance
  • Anergy
44
Q

What is deletion in terms of periphary?

A

Autoreactive T cells are deleted if the negativity is to much, instead of being deleted they can be “hired” to become Tregs.

Superantigens causes the deletion of the cell they are in, stap. b in mice

45
Q

What is ignorance in terms of the periphary?

A

T cells specific for self-antigens do not gain access to site where antigen is located.

In the example with LCMV, a LCMV mouse with inactive T cells was only activated when the strain came about. In this instance it means that the T cells IGNORED, the virus strain until there was an actual virus strain that the antigen could be presented to which would allow the activation of the disease and finally cause diabetes.

There are such things which are called immune privelaged sites where there are no immune system, testicles, brain stem.

46
Q

What is anergy?

A

Anergy is a term in immunobiology that describes a lack of reaction by the body’s defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance.

47
Q

How can anergy be reversed?

A

By signalling from IL-2 or OX40

48
Q

What are the routes to anergy?

A

Lack of co stimulation

Deprivation of amino acids, glucose, ATP and presence of adenosine

49
Q

How can a second graft B only be rejected when the intial graft a’s mDCs are inserted into the site of origin?

A

Inserting it into an immature tolerant body would expand the amount of APCs and create “an army”. Once new kidney graft is inserted than the torch from the graft A’s mDCs would shine on it as it would react. As it would have seen that the mDC was not self creating anti A clones for this. The original kidney would therefore still have some of these however spending the month in first graft B would have wiped them off there having no professional APCs. It wasnt until the mDCs came over that helped sign a light as such on the kidney and show that, that wasnt self.

50
Q

What are the peripheral tolerance in the B cells?

A

There are early checkpoints (PALS and germinal centres)

-receptor revision, deletion, anergy, ignorance

Late checkpoints

  • memory B cells
  • anergy etc.

Plasma cells

-poor competition for survival niches

Principles Of Pathology (8 decks)

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