Immunodeficiencies, tolerance and autoimmunity Flashcards
What is the definition of immunodeficiency?
Immunodeficiency is when the immune system fails to protect the host from disease causing
agents or malignant cells.
There are two types of immunodeficiency, which?
- Primary immunodeficiency: genetic or developmental defect. These diseases can be caused by defects in virtually any gene involved in immune development or function - innate or adaptive, humoral or cell-mediated. As one can imagine, the roles of the component that is missing or defective determine the degree and type of the immune defect; some immunodeficiency disorders are relatively minor, requiring little or no treatment, but others can be life-threatening and necessitate major interventions.
- Secondary (acquired) immunodeficiency: loss of immune function as a result from exposure to various agents. These agents include various diseases and infections, medical treatments such as with immunosuppressive drugs following organ transplantation, and social conditions that cause malnutrition. But by far the best known secondary immunodeficiency is acquired immunodeficiency syndrome (AIDS), which results from infection with the human
immunodeficiency virus (HIV).
How are primary immunodeficiencies categorized and grouped?
Primary immunodeficiencies can be loosely categorized as affecting innate or adaptive
responses and are often grouped by specific
components they affect. For example, NK deficiencies affect NK cells and so on.
Theoretically, any component important to immune function that is defective can lead to some form of immunodeficiency. Collectively, primary immunodeficiency diseases (PIDs) have helped immunologists to appreciate the importance of specific proteins and cellular processes that are required for proper immune system function.
Describe Severe Combined ImmunoDeficiency (SCID).
SCID is a family of disorders that stems from defects in lymphoid development leading to a lack of T cells in the periphery, which can affect both humoral and cell-mediated immunity as it also manifests as the absence of T cell–dependent B-cell antibody responses. One persons SCID is different from another.
The symptoms include severe recurrent infections & live-attenuated vaccines may be fatal. The condition is fatal, usually within the first year or two of life, unless infants receive immune-restoring treatments, such as transplants of blood-forming stem cells, gene therapy, or enzyme therapy. Otherwise they need a sterile environment to survive, which is practically impossible.
Give two examples of SCID disorders and what problems that arieses.
– Reticular dysgenesis (failure for both myeloid and lymphoid lineages to develop): Basically don’t have any immune cells (but they do have red blood cells), will die very quickly after birth unless HSC transplantation is done.
– Defective V(D)J recombination: failure to develop antigen specific BCRs and TCRs and thus only having the innate system to protect against diseases. Very susceptible to infections, especially those that are harder to defeat.
There are some immunodeficiencies that resemble SCID (lack of T cells), which? Think about what could cause a similar effect.
Bare-lymphocyte syndrome (BLS) which include two types of MHC deficiencies:
- Class I: No/reduced MHC class I expression, for example due to mutations in TAP genes leading to a reducing number of CD8+ T cells (suceptability to viruses and intracellular pathogens)
- Class II: No MHC class II molecules, often due to a defect in transcription factors activating MHCII gene expression, reducing numbers of CD4+ T cells. Symptoms very much resembling SCID, since Th cells are required for activation of CD8+ Tc cells, B cells.
Also Hyper-IgM syndrome, deficiency in CD40L, impairing communications between helper T cells and APCs, leading to reduced T-cell responses to intracellular pathogens and limited production of antibodies to T-dependent Ag (high levels of IgM but no class switching possible).
What is a common symptom with B cell immunodeficiencies?
Since the main function of B cells is to produce antibodies, deficient/lack of B cells lead to loss of all effector functions mediated by antibodies, mostly relating to extracellular pathogens like bacteria. The most basic effector functions of antibodies, neutralization to block binding and agglutination (aggregation which facilitates clearing are very important in keeping extracellular pathogens at bay, without these and the other effector functions that are more “active” in microbial clearance - recurrent bacterial infections will occur.
For example X-linked (Bruton’s) agammaglobulinemia - Block in B-cell development; no mature B cells.
If a patient comes in with recurrent bacterial and viral infections of respiratory, gastrointestinal and urogenital tract, what would likely be the cause?
Recurrent bacterial and viral infections of respiratory, gastrointestinal and urogenital tract points to a deficiency in IgA, which have a key role in microbial clearance and control in mucosal tissues.
IgA is found in all mucosal tissues and secretions and is very effective in neutralization and immune complex formation (agglutiation). IgA does NOT activate complement or drive inflammation, mainly because it’s present in mucus where commensal bacteria reside, that we don’t want to attack.
Give two examples of innate immunodeficiencies and why it is problematic.
- Selective NK-cell deficiencies: Absent or decreased total NK cells or NK subsets; or blocked synapse formation with target cells or problems with formation and function of cytotoxic granules –> increased susceptibility to viral infections and some cancers.
- Chronic granulomatous disease, Mutations in phagosome NADPH oxidase subunits –> No ROS or RNS for killing of phagocytosed pathogens –> the APCs can’t break down pathogen into peptides and present to T cells –> less adaptive response.
- Complement deficiencies (less defense against blood borne infections/extracellular microbes (mostly bacteria) depending on which complement protein is deficient the problems can vary from small to severe.
- Leukocyte adhesion deficiencies: Problems with leukocyte extravasation and chemotaxis, making them unable to enter infection sites and kill bacteria and other foreign invaders, leading to increases susceptibility to soft tissue infections.
Immunodeficiencies that disrupts immune regulation can manifest as autoimmunity, give one example.
Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) is an immunodeficiency caused by mutations in the AIRE gene. If the AIRE gene is not functional, this will lead to issues during negative thymic selection where T cells are tested for autoimmunity which allows escape of autoreactive T cells from the thymus, causing
organ-specific autoimmunity (for example Inhibition of endocrine function because of autoimmune attacks on endocrine organs) and can also cause reduced Treg formation, which normally works to minimize autoreactivity which exacerbates the autoimmunity symptoms.
Another example is IPEX syndrome, where mutated and inactive FoxP3 gene preventing
development and function of Treg cells, which also allows autoreactive T cells that escape the thymus to go unchecked. Can lead to immune destruction of bowel, pancreas, thyroid, skin
can result in death before 2 years of age.
Immunodeficiencies are often detected early in life, but not in newborns necessarily, why?
Newborns still have passive immunity in the form of IgG from the mothers milk, but still susceptible to viral infections. Overall recurrent infections early in life is a really red flag and indicates some immunodeficiency.
How are immunodeficiency disorders usually treated? Give three examples.
Immunodeficiency disorders are treated by replacement therapy!
Replacement of a missing protein (but this requires recurring treatments, expensive)
– Passive Ig injection (quite common, especially for those disorders that disrupt antibody
responses.)
– Production and injection of recombinant proteins (e.g. rIFN-γ) - very expensive
Replacement of a missing cell type or lineage
– Bone marrow or HSC transplantation
Replacement of a missing or defective gene
– Gene therapy
What are the most common animal models for studying immunodeficiencies?
Animal models for immunodeficiency include nude, RAG KO and SCID mice possessing one or several defects and that have varying levels of immunodeficiency.
- Nude mice have no Thymus –> no T cells.
- RAG KO mice have no B or T cells
- Certain SCID mouse strains have been generated with multiple mutations so that they are deficient in B, T, and NK cells.
These are usually the mice of choice for generating mice with humanized immune systems following transfer of human
hematopoietic stem cells.
What is the most well known secondary immunodeficiency disease?
Acquired ImmunoDeficiency Syndrome (AIDS) is by far the most well understood.
Other examples
- Acquired hypogammaglobulinemia (unknown origin)
- Agent-induced immunodeficiency (chemical, biological agents that induce an immunodeficient state)
- can also be caused by malnutrition, aging, medications, treatments etc. In most cases this kind of acquired immunodeficiencies can be reversed, but not yet in HIV/AIDS.
What symptoms did AIDS patients present with?
Patients presented with opportunistic fungal infections, rare tumors and significantly
decreased numbers of CD4+ T cells.
Which cells does HIV infect? How?
HIV selectively infects CD4+ cells, which is mainly Th cells but other cells also express CD4, monocytes, macrophages and dendritic cells.
HIV infects CD4+ cells by binding to the CD4 proteins as well as a chemokine receptor (CCR5 or CXCR4) which allows the outer membrane of the virus to fuse with the cell membrane.
Dendritic cells in virus-exposed areas may take up and harbor virus, passing it to CD4+ T cells – the infectious synapse!
NOTE: HIV that cause infections, called R5 viruses, usually use the CCR5 coreceptor, found on effector memory T cells, macrophages, and dendritic cells common in mucosal epithelia. These R5 viruses are the major virus type through much of the early infection period.
As the infection progresses, R5 viruses may mutate to preferring the CXCR4 coreceptor, enabling them to infect naïve as well as central memory T cells. These X4 viruses contribute to the later significant decline in numbers of CD4 T cells.
Explain the correlation between HIV and AIDS in an untreated patient.
Infection with HIV leads to gradual impairment of immune function, initially after infection, the viral load will peak and the CD4+ T cells will fall. Then, as immune responses attack, the viral load will fall, leading to a slight increase in CD4+ T cells. This is the acute phase - weeks. In this phase, there are no antibodies, which makes it hard to diagnose.
The asymptomatic phase can then go on for years, with a falling number of CD4+ T cells and a slowly rising viral load.
Then, when the CD4+ T cells are getting too low, the patient will get AIDS which usually results in death from opportunistic infections or cancers. Because of the low number of Th cells that cant activate the adaptive immunity well and no Tc cells that can kill the virus infected cells are activated. Death is often because of infection without good response.
Describe how HIV interferes with immune function in different aspects.
The gradual loss of Th cells will lead to low humoral responses as B cells can’t be activated (only TI activation, which requires TI antigens), also, CTLs will decrease, especially as the virus mutates and switch spike proteins - for which the pre-existing CTLs from the early response are not effective against anymore. The lack of Th cells can’t activate CD8+ T cells much, which leads to a decreasing adaptive response and gradual loss of immune structures. All of this leads to more infections by opportunistic pathogens, which eventually will lead to death.
How do we treat HIV?
- There are medications that are so good that you can live with undetectable levels of HIV (thus not being infectious) for a long time.
- There are also really good medications for HIV infected mothers that hinders transmission of HIV to the child.
Unfortunately these treatments are expensive and not available to all - also, resistance to these medications can make them ineffective.
What is tolerance?
Tolerance: prevention of an immune response against self structures.
In other words, individuals should tolerate - or not respond aggressively against - their own antigens, although their immune systems will attack pathogens or even cells from another individual.
There are two tolerance mechanisms at work to establish and maintain tolerance, which?
- Central tolerance: deletion of self-reactive lymphocytes before they mature. Takes place in the primary lymphoid organs.
- Peripheral tolerance: either renders self-reactive lymphocytes nonresponsive (anergy), induces apoptosis or actively generates inhibiting lymphocytes (pTregs). Takes place in the periphery.
Note: The inactivation of an immune response does not result in general immune suppression, but rather inhibition specific for the tolerogenic
antigen, presented in a nonimmunogenic context. Context matters! a tolerogenic response in mucosal tissues might elicit an immune response in circulation.
Besides cellular tolerance mechanisms, there are other ways to evade the immune system to avoid self reactivity, give an example.
Antigen sequestration/partitioning is one means to protect self-antigens from attack.
For example, the anterior chamber and lens of the eye are considered sequestered sites, with little or no lymphatic drainage. The tissue-specific antigens that are expressed in these “privileged sites” are at least partially isolated from interaction with many elements of the immune system (not total isolation, some immune cells are present - probably biased to tolerance rather than assault.).
Sequestration allows these antigens to evade encounter with reactive lymphocytes under normal circumstances; if the antigen is not exposed to immune cells, there is little possibility of reactivity. The downside to this is that if these barriers are breached, e.g. by trauma, the newly exposed antigen may be seen as foreign and aggressively attacked by immune responses, which high local damage potential, leading to inflammation, tissue destruction, and impaired vision (in the eye).
How does central tolerance limit development of autoreactive T and B-cells in relation to their antigen specific receptors?
During T cell development in the thymus, once the TCR has successfully formed, further receptor editing is blocked to ensure that mature T cells that have gone through the selection processes don’t become auto-reactive later. High affinity for self-Ag results in induction of apoptosis in B and T-cells during the selection processes.
B cells on the other hand are allowed to undergo receptor editing in the germinal center, to make it possible to produce high affinity antibodies toward the antigen. This makes it possible for B cells to produce auto-reactive antibodies, but this is not nearly as detrimental as having autoreactive CTLs. This is a trade off which is tolerated because of the importance to produce high affinity antibodies against pathogens. Although, when mature B cells encounter most soluble antigens in the absence of T-cell help, they become anergic and never migrate to germinal centers. In this way, maintenance of T-cell tolerance to self antigens enforces B-cell tolerance to the same antigens.
Regulatory T cells have a central role in peripheral tolerance, in short, how are they generated and what is their mechanism of action?
Tregs are developed from CD4+ T cells with high affinity to self antigens in the thymus and express the FoxP3 transcription factor, a hallmark of this cell type (tTregs (thymic emigrant Tregs)), or in the periphery following self-Ag induction (i/pTregs).
Tregs still engage Ag-MHC class II complexes through TCR interactions, but down regulate responses when they do. They also eliminate self reactive T cells in the periphery.
Tregs work via contact dependent and intependen mechanisms, explain each.
CD4+ Tregs work via contact dependent and independent mechanisms:
- Contact dependent mechanisms occur as TREG cells express high levels of inhibitory CTLA-4 molecules with high affinity to CD80/86 (compared to CD28 that is activating), to shut down autoreactive cells. CTLA-4 can also downregulate APCs through inhibition of pro-inflammatory cytokine secretion.
- Independent mechanisms rely upon secretion of cytokines (IL-10, TGF-β, IL-35) into the surrounding area, shutting down nearby cells’ responses. (this is very important in having tolerance to commensal microbiome too).
Does regulatory B cells exist?
Yes, but the B cells with regulatory activity found show no clear pattern of surface molecules or sole function, so they are difficult to nail down. Regulatory B cells (BREGs) may exist, producing IL-10 as an inhibitor of adaptive immunity – still being studied/clarified.
In mouse models of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, animals engineered with B cells incapable of secreting IL-10 showed chronic T 1-cell activation and a worsening of the disease. While B cells are certainly not the only cells that can make IL-10, it is clear that B cells are important inhibitors of adaptive immunity.
Also Myeloid-derived suppressor cells (MDSCs) (often macrophages) may secrete inhibitory compounds such as IL-10, indoleamine 2,3-dioxygenase (IDO), arginase1, and inducible nitric oxide synthase (iNOS) to negatively regulate autoimmunity. These cells may also express immunosuppressive surface markers such as PD-L1.
What causes autoimmune diseases?
Autoimmune disease is caused by failure of the tolerance processes, leading to autoreactivity with subsequent destruction of self proteins, cells, and organs by auto antibodies or self-reactive T cells.
Autoimmunity may be organ specific or systemic and may involve antibodies, T cells, immune complexes, or any combination of elements. It can also involve innate immunity.
Often chronic and debilitating, these diseases can lead to morbidity and mortality from complications, including prolonged medical intervention.
Give three examples of organ specific autoimmune diseases.
- Hashimoto’s thyroiditis
- Myasthenia gravis
- Type 1 diabetes mellitus
Briefly explain Hashimoto’s thyroiditis.
Hashimoto’s thyroiditis is a organ specific autoimmune disease that is caused by production of autoantibodies and sensitized TH1 cells specific for thyroid Ag. Ab produced interferes with iodine uptake and decreases thyroid function leading to hypothyroidism. Induction of TH1 responses in the thyroid lead to inflammation, which results in goiter - visible enlargement of the thyroid gland. More common in women.
Treatment with thyroid hormones daily.
Briefly explain Myasthenia gravis.
In Myasthenia gravis, autoantibodies that bind acetylcholine receptors on motor end plates of muscles are produced. These autoantibodies block the normal binding of acetylcholine, and induce complement- mediated lysis that cause their destruction. The lack of acetylcholine stimulation result in progressive weakening of skeletal muscles which don’t receive any signals.
Treatments are aimed at increasing acetylcholine levels (e.g., using cholinesterase inhibitors), decreasing antibody production (using corticosteroids or other immunosuppressants), and/or removing antibodies (via plasmapheresis: the removal and
exchange of blood plasma).
Briefly explain Type 1 diabetes mellitus.
Type 1 diabetes mellitus is caused by an autoimmune attack against insulin-producing beta cells in the pancreas, resulting in the destruction of beta islet cells with subsequent decrease in insulin secretion –> increased blood glucose levels requiring life-long treatment with insulin.
The disease starts by CTLs that infiltrate the pancreas and activate macrophages (sort of like an DTH response). This is followed by cytokine release and production of autoantibodies, which may activate complement or ADCC activities by NK cells.
Give three examples of systemic autoimmune diseases.
- Multiple sclerosis
- Rheumatoid arthritis
- Systemic lupus erythematosus (SLE)
Briefly describe Multiple sclerosis.
Multiple sclerosis result from having autoreactive CD4+ T cells, mainly with Th17 cells and the IL-17 they secrete as a hallmark, that recruit B cells that secrete autoreactive antibodies and interact with microglia that secrete pro-inflammatory cytokines –> leading to the formation of inflammatory lesions along myelin sheaths around nerve fibers in the brain and spinal cord. This breakdown of myelin leads to a range of symptoms, from numbness to paralysis and loss of vision.
Briefly describe Rheumatoid arthritis.
Individuals with rheumatoid arthritis produce auto-reactive antibodies called rheumatoid factors (RFs), which are specific for the Fc region of IgG—in other words, antibodies against antibodies! (IgM antibodies most common). When these RFs bind to normal circulating IgG, immune complexes form and are deposited in the joints. These can activate the complement
cascade, resulting in a type III hypersensitivity reaction and chronic inflammation of the joints.
Treatments include nonspecific anti-inflammatory drugs and corticosteroids. Recently more specific anti-cytokine antibodies have also been introduced as treatment.
Briefly describe Systemic lupus erythematosus (SLE).
In Systemic lupus erythematosus (SLE), auto antibodies towards a vast array of cells or common cellular components, such as DNA and histones, as well as clotting factors, RBCs, platelets, and even leukocytes. Signs and symptoms include fever, weakness, arthritis, kidney dysfunction, and frequently skin rashes, especially the characteristic butterfly rash across the nose and cheeks. When immune
complexes of auto-antibodies with various nuclear antigens are deposited along the walls of small blood vessels, a type III hypersensitivity reaction develops which causes tissue damage.
Can be detected by fluorescently labeled secondary antibodies directed against human antibodies are added and reveal staining of the nucleus, and thus presence of anti-nuclear antibodies.
Why do we think autoimmunity is so much more common in women than in men?
Evidence suggests that females have enhanced immune responses than men overall, which is apparent when looking at innate immune responses, humoral (more antibodies produced) and cell-mediated in women vs men. This enhanced immunity seem to some at a price, higher risk of developing autoimmune disease. Sex hormones also seem to play a role, it seems like estrogens have enhancing effects of immunity while androgen are more suppressive. Also during pregnancy, the immune system is modified to be biased towards Th2 responses rather than Th1 as usual (probably to better tolerate the fetus, which is sort of like an allogenic graft) which increases the risk of SLE which is enhanced by Th2 responses.
Give three examples of intrinsic factors (intrinsic/extrinic) that increases suscepability to autoimmune diseases.
Intinsinc (genetic)
- Certain MHC genes are linked to specific autoimmune disorders, since deficiencies in MHC will affect tolerance establishing pathways (as self-antigens can’t be presented) which makes one more susceptible to autoimmunity.
- Mutations in AIRE and FoxP3 genes result in particular immunodeficiencies that affect central and peripheral tolerance, which can lead to the development of autoimmunity.
- Genes that encode for cytokines, for example those that influence differentiation of Th17 cells (involved in the Th1) response, are linked to autoimmunity. Having uncontrolled Th1 or Th2 responses is not good and can lead to autoimmunity.
Extrinsic:
- Sex (women more susceptible)
- diet and the mucosal flora
- obesity, smoking, infection
Several animal autoimmune disease models exist, give one example.
Most animal autoimmune disease models are transferable by T cells.
- Nonobese diabetic (NOD) mouse (used for studying Type 1 diabetes (T1D)), transferable by T cells.
- Obese-strain chicken are used to study Hashimoto’s thyroiditis, transferable by T cells.
Certain CD4+ T cells are especially indicated to have a big role in autoimmunity, which?
- Th1 cells secreting INF-g
- Th17 cells secreting IL-17 (eg in psoriasis)
-Th2 cells in atopic dermatitis (hypersensitivity)
The exact causes for autoimmunity is not established, but it often seem to be induced, give two examples of things that could potentially induce autoimmunity.
Induction of autoimmune disease may be multifactorial - combining a series of triggering events that cross an individual’s systems of tolerance over a threshold:
- Infections and molecular mimicry
- Infections that induce genetic changes
- Damage/stress events that expose sequestered Ag
- Foods that alter gut microbial balance, promoting chronic inflammation and hypersensitivity reactions, gluten.
- toxins/UV light
- increase in surrounding nucleic acids, eg. from killed cells etc that are stabilized and can form immune complexes.
How do we treat autoimmunity?
Autoimmunity can’t be cured but we can manage and alleviate the symptoms, often through immunosuppression.
- monoclonal antibodies toward autoreactive antibodies.
- Therapies that block steps in the inflammatory process, e.g. drugs that block TNF-α are used to treat RA, psoriasis, and Crohn’s disease
- Strong anti-inflammatory drugs that inhibit lymphocyte proliferation or kill the cells
- General toxicity is a negative side effect
- Also predisposes individuals to uncontrolled infections
- Can promote development of cancer by removing antitumor T and NK cells
- Organ removal may also alleviate some symptoms in certain cases, good if you can live without the organ affected.
- The Holy Grail — Antigen-specific immunotherapy aimed to stimulate tolerance to the auto-Ag, restoring balance. For example increasing Tregs, and regulatory B cells and APCs. Not there yet.
