IAS57 The Immune System in Health Disease

Tumor cells can 'sneak through' the immune system by employing various mechanisms that allow them to avoid detection and destruction by immune cells.

Tumor cells often lack key molecules that are important for immune recognition, which helps them evade immune responses.

Tumor-derived factors can suppress immune responses, creating an immunosuppressive environment that allows tumors to grow and spread without being attacked by the immune system.

PD-L1 binds to PD-1 on T cells, inhibiting their ability to kill tumor cells.

They block the interaction between PD-L1 on tumor cells and PD-1 on T cells, allowing T cells to effectively kill tumor cells.

T cell activity is inhibited, preventing the T cell from killing the tumor cell.

Blocking PD-L1 or PD-1 allows T cells to kill tumor cells, leading to tumor cell death.

CTLA-4 binds to B7-1/B7-2 on antigen-presenting cells, inhibiting T cell activation.

Blocking CTLA-4 with an Anti-CTLA-4 antibody allows T cells to become active and kill tumor cells.

Key molecules include B7-1/B7-2 on antigen-presenting cells, CTLA-4 and CD28 on T cells, and MHC with antigen binding to TCR on T cells.

The activation of T cells leads to tumor cell death.

Hypersensitivity is a state of heightened reactivity to innocuous antigens, also known as allergens, which can lead to adverse immune responses.

Autoimmunity refers to an adaptive immune response that is directed against self-antigens, resulting in the immune system attacking the body's own tissues.

Current classifications of primary immunodeficiency include:

• Immune dysregulation: hemophagocytic lymphohistiocytosis (HLH) & EBV susceptibility
• Syndromes with autoimmunity: e.g. IPEX
• Innate immunity defects: e.g. Mendelian Susceptibility to Mycobacterial Disease (MSMD)
• Autoinflammatory disorders: e.g. familial Mediterranean fever
• Associated with somatic mutations or auto-antibodies: e.g. anti-IFNy antibody

1. Immunity against infectious agents: Protects the body from pathogens like bacteria and viruses.

2. Immunity against 'non-self': Involves responses to allergens and mechanisms related to transplantation immunity.

3. Immunity against 'self': Includes processes related to autoimmunity and anti-tumor immunity.

Genetic mutations can be either inherited or acquired.

• HPV is associated with cervical cancer.
• HBV is associated with hepatocellular carcinoma (HCC).

Immunodeficiency can lead to cancers such as Kaposi's sarcoma and Burkitt's lymphoma.

Vaccines against viruses can prevent certain cancers by targeting the viral infections that may lead to tumor development.

Neonatal or old age individuals show different immune responses compared to adults, which can affect tumor immunity and susceptibility.

Evidence includes immune cell infiltration in tumors, spontaneous regression of tumors, and postmortem findings showing more tumors than those clinically diagnosed.

GVL response refers to the immune response where transplanted immune cells attack leukemia cells, demonstrating the potential of the immune system in targeting tumors.

Blood is drawn from the patient to obtain T cells.

The CAR (Chimeric Antigen Receptor) gene is inserted into the T cells to create CAR T cells.

The CAR T cells are grown in millions before being infused back into the patient.

CAR T cells bind to cancer cells and kill them.

CAR stands for Chimeric Antigen Receptor.

The tumor surveillance theory suggests that the immune system continuously monitors and eliminates tumor cells, preventing the development of cancer. However, some tumor cells can evade this surveillance.

1. Immunity against infectious agents
2. Immunity against 'non-self' (e.g., allergy, transplantation immunity)
3. Immunity against 'self' (e.g., autoimmunity, anti-tumor immunity)

The principle of vaccination involves introducing a harmless form of a pathogen or its components to stimulate the immune system, leading to the development of protective immunity. This prepares the immune system to recognize and combat the actual pathogen upon future exposure.

The immune effector mechanisms against infections include:

1. Phagocytosis - Engulfing and destroying pathogens by immune cells like macrophages and neutrophils.
2. Antibody production - B cells produce antibodies that neutralize pathogens and mark them for destruction.
3. Cell-mediated immunity - T cells directly kill infected cells or help other immune cells respond effectively.
4. Cytokine release - Signaling molecules that coordinate the immune response and enhance the activity of immune cells.

Immunodeficiency refers to a state where the immune system's ability to fight infections is compromised or entirely absent. This can lead to increased susceptibility to infections, prolonged illness, and a higher risk of opportunistic infections. Immunodeficiencies can be primary (genetic) or secondary (acquired due to factors like infections, malnutrition, or medical treatments).

• Speed: Early and rapid response
• Strength: Limited in strength
• Specificity: Non-specific response
• Components: Includes macrophages and NK cells

• Speed: Takes time to develop
• Strength: Powerful response
• Specificity: Highly specific to pathogens
• Memory: Capable of remembering past infections
• Components: Involves B and T lymphocytes

In the first infection, the immune response is slow, allowing pathogens to proliferate and cause disease and symptoms. In the second infection, the response is fast, neutralizing the virus before symptoms appear, resulting in no disease or symptoms.

During the first attack of measles, adaptive immunity is too slow to prevent the virus from growing, leading to the development of symptoms.

In a second attack of measles, the antibody response is able to neutralize the virus before symptoms appear, preventing disease.

The general principle is that the first infection leads to a slow response while subsequent infections trigger a fast response, with some exceptions such as HIV.

The principle of vaccination involves introducing a toxoid to stimulate an immune response, leading to the formation of memory cells. This results in a quicker and more effective antibody response upon subsequent exposure to the actual toxin from a natural infection, which typically elicits a larger and delayed antibody response.

In vaccination, the antibody response initially rises to a peak and then declines, while in natural infection, the antibody response peaks later and is generally higher. This demonstrates the effectiveness of vaccination in preparing the immune system for future exposures.

Memory cells are formed during vaccination and are crucial for providing acquired immunity. They enable a faster and more robust antibody response upon re-exposure to the pathogen, compared to the response generated by a natural infection.

The secondary immune response features a short lag time of 1-4 days and an early peak of antibody production within 3-5 days. It lasts longer and is significantly stronger, producing 100-1000 times more antibodies compared to the primary response. This response is facilitated by memory B cells and is similar for T cell responses.

Only thymus (T) dependent antibodies are produced during the secondary immune response.

The secondary immune response mainly occurs in the bone marrow.

The antibodies produced in the secondary immune response have high antibody affinity.

Affinity maturation occurs due to somatic hyper-mutation of Ig variable region genes.

The primary antibody class involved in the secondary immune response is IgG, due to antibody class switching.

Somatic hypermutation is a process that generates antibody diversity by introducing mutations in the immunoglobulin genes of B cells. This process occurs in somatic cells and is mediated by Activation Induced Cytidine Deaminase (AID). The mutations lead to the production of antibodies with higher affinity for the antigen during the secondary immune response.

Somatic hypermutation increases the affinity of antibodies for their specific antigens. During the secondary immune response, B cells that have undergone somatic hypermutation are selected for based on their ability to bind more effectively to the antigen, resulting in a more robust immune response.

Activation Induced Cytidine Deaminase (AID) is crucial for somatic hypermutation as it initiates the mutation process in the immunoglobulin genes of B cells. AID specifically targets somatic cells, leaving germ cell DNA unaffected, which is essential for maintaining genetic stability in the germline.

The primary region includes genes in the heavy chain locus labeled as V, DJ, mu, gamma 1, gamma 2b, gamma 2a, epsilon, and alpha.

Enzyme activity removes DNA segments between switch regions, specifically excising the mu, gamma 3, and gamma 1 segments.

Non-homologous end joining of DNA occurs at the switch regions to rejoin the remaining segments.

The genes include V, DJ, gamma 1, epsilon, and alpha, with the transcript labeled as IgG1.

The excised DNA segment consists of looped blocks labeled as gamma 2b and gamma 2a, which are removed during the switching process.

Vaccination works by stimulating the immune system to recognize and remember specific pathogens, thereby providing protective immunity against future infections. This is achieved by introducing a harmless component of the pathogen, such as an inactivated virus or a piece of its genetic material, which prompts the immune system to produce antibodies and memory cells.

The immune system employs several effector mechanisms to combat infections, including:

1. Antibody production: B cells produce antibodies that neutralize pathogens.
2. Cell-mediated immunity: T cells, including cytotoxic T cells, directly kill infected cells.
3. Phagocytosis: Phagocytes, such as macrophages and neutrophils, engulf and destroy pathogens.
4. Cytokine release: Immune cells release cytokines to coordinate the immune response and recruit additional immune cells to the site of infection.

• Prokaryotic: They lack a cell nucleus.
• Can be extracellular or intracellular.

• Eukaryotic: They have a cell nucleus.
• Can be single-celled or multi-cellular (e.g., yeasts, molds).

• Host dependent: They rely on a host for survival.
• Include worms and protozoa.

• They can only replicate in living cells, making them intracellular.
• Include both RNA and DNA viruses.

The two main types of pathogens are extra-cellular pathogens and intra-cellular pathogens.

The two types of immune responses are humoral responses and cell-mediated responses.

Type 1 interferon acts as a signal to induce an antiviral state in target cells, helping to protect against viral infection.

Natural killer (NK) cells attack and kill infected cells, leading to the eradication of established infections.

B cells produce antibodies that neutralize the virus, contributing to humoral immunity.

CD8+ CTLs attack and kill infected cells, providing cell-mediated immunity against viral infections.

The components of non-specific humoral immunity include:

• Complements
• Histamine
• Acute phase proteins

The specific functions of antibodies in humoral immunity include:

1. Neutralization: Targeting viruses and toxins.
2. Opsonization: Binding pathogens for recognition by immune cells, such as phagocytes.
3. Promoting complement-mediated lysis: Enhancing the destruction of pathogens through the complement system.

Perforins and granzymes play a role in both non-specific and specific humoral immunity by:

• Perforins: Creating pores in the membranes of target cells.
• Granzymes: Inducing apoptosis in infected or cancerous cells.

Cytokines and chemokines function in humoral immunity by:

• Cytokines: Acting as signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis.
• Chemokines: Attracting immune cells to sites of infection or inflammation, facilitating the immune response.

The components include:

1. Phagocytes
2. Macrophages (MQ)
3. Natural killer cells (NK)

• Cytotoxic T cells (Tc): Kill infected cells.
• Helper T cells (TH): Help other cells in the immune response.

In non-self recognition, a cytotoxic T lymphocyte (CTL) interacts with a target cell through its T cell receptor (TCR) binding to an MHC class I molecule on the target cell. The CTL also expresses CD8, which aids in this recognition process.

In missing self recognition, a natural killer (NK) cell interacts with a target cell that lacks MHC class I. The NK cell's inhibitory receptors are not activated due to the absence of MHC class I, allowing tonic activating ligands to engage with NK receptors, which triggers the NK cell to kill the target cell.

MHC class I molecules are crucial for the recognition of self versus non-self by CTLs. They present peptide fragments to TCRs on CTLs, facilitating the identification of infected or abnormal cells.

Inhibitory receptors on NK cells prevent them from attacking healthy cells that express MHC class I. When MHC class I is absent, these receptors do not get activated, allowing NK cells to initiate cytotoxic activity against the target cell.

• Pattern recognition receptors (PRRs): Found in Dendritic cells, macrophages, monocytes, neutrophils, epithelial cells. Targets Pathogen-associated molecular patterns (PAMPs) and Damage-associated molecular patterns (DAMPs).
• A variety of activating or inhibitory receptors: Found in Natural killer cells (no MHC restriction).

• T cell receptor: Found in T-helper (Th) and T-cytotoxic (Tc) lymphocytes. Targets Specific Antigen (Ag) + MHC class II (Th) or class I (Tc).
• B cell receptor (surface Ig): Found in B lymphocytes. Targets Specific Antigen (Ag).

PRRs, or Pattern Recognition Receptors, are host receptors that detect foreign microbial molecules known as PAMPs. They play a crucial role in recognizing 'non-self' entities to initiate an immune response.

The two types of PRRs are:

1. Membrane-bound PRRs: Located on the cell surface, examples include Toll-like receptors (TLRs) and C-type lectin receptors (CLRs).

2. Cytoplasmic-bound PRRs: Located inside the cytoplasm, examples include NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs).

PAMPs, or Pathogen-Associated Molecular Patterns, are molecular signatures found only on microbes and not on host cells. They are important because they allow the immune system to recognize and respond to foreign pathogens, distinguishing them from self-cells.

Examples of PAMPs include:

• Bacterial carbohydrates: e.g., lipopolysaccharide (LPS), mannose (from Gram-negative bacteria)
• Nucleic acids: e.g., viral RNA, bacterial DNA (from viruses/bacteria)
• Bacterial peptides: e.g., flagellin, microtubule elongation factors (from bacterial flagella)
• Gram-positive bacterial wall components: e.g., peptidoglycan, lipoteichoic acid (from Gram-positive bacteria)

Bacterial carbohydrates are recognized by:

• Receptors: TLR4, mannose receptor
• Source: Gram-negative bacteria (e.g., LPS, mannose)

Nucleic acids are recognized by:

• Receptors: TLR3, TLR7, RIG-I
• Source: Viruses and bacteria (e.g., viral RNA, bacterial DNA)

The functions of PRRs are:

• Membrane-bound PRRs: Detect extracellular pathogens or their products.
• Cytoplasmic-bound PRRs: Detect intracellular pathogens, such as viral RNA and bacterial cell wall fragments.

1. CD16+ CD56dim/neg: These are cytotoxic NK cells, making up about 90% of NK cells.

2. CD16-CD56 bright: These are regulatory or cytokine-secreting NK cells.

Natural killer (NK) cells can be distinguished using specific stains that identify their surface markers:

• CD16+ CD56dim/neg for cytotoxic NK cells
• CD16-CD56 bright for regulatory NK cells.

Natural killer (NK) cells are somewhat similar to T cells in function:

• Cytotoxic NK cells are similar to cytotoxic T cells (CD8+).
• Regulatory NK cells are similar to **helper T cells (CD4+).

Killer cell releases perforins (穿孔素).

Perforins form pores in the target cell membrane, allowing substances to enter the cell.

Water influx leads to osmotic lysis (滲透性裂解) of the target cell.

Granzymes (顆粒酶) enter through the pores formed by perforins and activate caspases (天蛋白酶), leading to apoptosis.

1. Killer cell expresses Fas ligand (FasL)
2. FasL binds to Fas receptor (CD95) on target cell
3. Binding activates caspase cascade
4. Leads to DNA fragmentation, endonuclease activation, and apoptosis.

Tc cells kill infected cells using Perforin and Granzymes.

Th1 cells secrete IL-2 and IFN-γ, which promote type IV (delayed) hypersensitivity.

Th2 cells secrete IL-4 and IL-10, promoting type I (immediate) hypersensitivity.

IL-17 is a pro-inflammatory cytokine essential in fighting extracellular pathogens and fungi.

T helper (TH) cells play a central role in immune responses by:

1. Activating Antigen-Presenting Cells (APCs): TH cells are activated when an antigen is presented to them by APCs.

2. Releasing Cytokines: Once activated, TH cells release cytokines that stimulate various immune cells, including:

   • Tc cells (cytotoxic T cells)
   • NK cells (natural killer cells)
   • Macrophages
   • Granulocytes

3. Stimulating B Cells: TH cells also stimulate B cells, which upon activation, release antibodies.

4. Facilitating Antibody-Dependent Cell-mediated Cytotoxicity (ADDC): The antibodies released by B cells interact with K cells to facilitate ADDC.

The CD4+ T cell counts show an initial sharp decline after infection, followed by a recovery phase, and then a gradual decrease over several years until reaching very low levels at the AIDS stage.

The dashed horizontal line at approximately 200 indicates immune deficiency, which is a critical threshold for CD4+ T cell counts in HIV infection.

The stages of HIV infection indicated on the X-axis are: Infection, Seroconversion, 2-6 weeks, mean of ~10 years, Symptomatic phase, and AIDS.

The area labeled 'Depletion of CD4 T cells' indicates the progressive loss of CD4+ T cells over the course of HIV infection, which is critical for understanding the disease's impact on the immune system.

The 'Flu-like disease (sometimes)' phase refers to the initial symptoms that may occur shortly after HIV infection, often during the acute phase of the disease.

Type I interferons (IFN-α/β) are produced by virus-infected cells. Their main functions include:

• Inducing anti-viral activities in cells
• Activating large granular lymphocytes (LGL), specifically natural killer (NK) cells
• Enhancing MHC Class I expression.

Type II interferons (IFN-γ) are produced by NK and T cells. Their key roles include:

• Inducing anti-viral activities in cells
• Activating macrophages
• Stimulating IL-12 production
• Stimulating nitric oxide (NO) production
• Enhancing MHC Class I and II expression
• Directly killing infected cells.

TH1 cells activate macrophages through the secretion of IFN-γ (Interferon-gamma). This activation enhances the macrophages' ability to respond to pathogens.

Activated macrophages produce IL-12, which further activates TH1 cells, and they also enhance MHC expression, promote phago-lysosomal fusion, and induce nitric oxide synthase (iNOS), which helps in stopping proliferation of pathogens.

Key outcomes include:

1. IL-12 production
2. Increased MHC expression
3. Phago-lysosomal fusion
4. Inducible nitric oxide synthase (iNOS) activation
5. Inhibition of pathogen proliferation

Cytokines, such as TNF-alpha, TNF-beta, and IFN-gamma, mediate the process of direct target cell killing by cytotoxic cells. They facilitate the interaction between cytotoxic cells and target cells, leading to the lysis of the target cells.

The main types of phagocytes are macrophages and granulocytes.

The first step in phagocytosis is chemotaxis, where phagocytes are attracted to the site of infection by chemotactic components and fragments.

During the 'attachment and uptake' phase, the phagocyte attaches to and engulfs the bacterium, incorporating it into the cell.

In the 'destruction' phase, the phagocyte completely engulfs the bacterium, which is then contained within a vacuole inside the phagocyte.

Reactive Oxygen Intermediates (ROIs) are molecules that play a crucial role in the immune response by helping to kill microorganisms. An example of an ROI is the superoxide anion.

Reactive Nitrogen Intermediates (RNIs) are important in the immune response for killing pathogens. An example of an RNI is nitric oxide.

Other mediators involved in phagocyte-mediated killing include Lysozyme and Prostaglandins.

Cytokines involved in phagocyte-mediated killing include IL-1, IL-6, TNF, and IFN-γ.

The primary defect in CGD is in NADPH oxidase, leading to defective production of reactive oxygen species (ROIs) in neutrophils and monocytes.

Chronic Granulomatous Disease can be inherited in the following patterns:

The gene most commonly associated with X-linked Chronic Granulomatous Disease is CYBB, which encodes the electron transport protein gp91phox.

The two main types of immunodeficiencies are Primary and Secondary immunodeficiencies.

Primary immunodeficiencies are intrinsic and are most often genetically linked. An example is Severe Combined Immunodeficiency (SCID), which is characterized by a lack of T and B cells.

Secondary immunodeficiencies are extrinsic and acquired. Causes include:

1. Infections (e.g., AIDS caused by HIV infecting T helper cells)
2. Drugs (immunosuppressive medications)
3. Irradiation (radiation therapy)
4. Malnutrition

Recurrent pyogenic infections can be caused by:

1. Defects in immunoglobulins
2. Defects in complements
3. Defects in phagocytosis
4. Pathogens: primarily encapsulated bacteria

Defective cell-mediated immunity (CMI) is associated with opportunistic infections, which are caused by common pathogens such as viruses and yeast.

An opportunistic pathogen is a microorganism that causes infectious disease only in individuals with compromised host defense mechanisms.

The traditional types of primary immunodeficiency include:

1. T cell deficiencies
2. B cell deficiencies
3. Combined T and B cell deficiencies
4. Phagocyte deficiencies
5. Complement deficiencies

In immunology, 'self' refers to the body's own tissues and cells, while 'non-self' refers to pathogens and foreign substances that the immune system targets. A healthy immune system effectively responds to non-self entities but does not attack self tissues under normal conditions.

The mechanisms of self-tolerance include:

1. Central tolerance: Also known as 'Thymic education', where T cells that react strongly to self-antigens are eliminated during their development in the thymus.
2. Peripheral tolerance: This involves failed-safe mechanisms, such as the action of Treg cells (regulatory T cells) that suppress the activity of other immune cells to prevent autoimmunity.