Lecture 39: Factors Influencing Immune Responses

Question 1

What is Immunodeficiency and what are some classifications of Immunodeficiency?

Answer 1

Immunodeficiency disorders result in a full or partial impairment of the immune system.

The immune system has many components, including antibodies, complement, B and T lymphocytes, cytokines and their receptors, adhesion and other accessory molecules, HLA antigens, phagocytes etc.

Malfunction of any may result in a state of immunodeficiency which may be:

• Congenital (primary) due to a genetic defect or in utero disease
• Acquired (secondary) may be secondary to drug therapy (steroids, cytotoxic drugs), or systemic disease (renal failure, malnutrition, malignancy, burns), or infection (e.g. HIV).

Alternatively, immunodeficiency can be classified as:

• Primary (inherited/genetic) such as selective IgA deficiency (1/500) commonly, but other primary IDs are rare. The body’s resistance to infection is much more likely to be compromised secondary to medication or to other diseases.
• Secondary due to some other factor such as HIV

Immunodeficiency can also be classified according to part of immune system affected (humoral, cellular, combined, complement, and phagocytic).

Question 2

Immunodeficiencies are typically revealed by…..

Answer 2

You should suspect ID whenever a patient has _(1) recurrent bacterial infection_s, or (2) infections with unusual organisms.

Question 3

Describe the type of Organism and the Immunological Responses to these organisms

1) Ex bacteria
2) Int bacteria
3) Viruses
4) Parasites
5) Fungi

Answer 3

Immunodeficiency states usually present clinically with infection. Type of infection is a clue to underlying immune defect, but is usually not in itself diagnostic. Certain immune mechanisms are important for different organisms.

You should suspect ID whenever a patient has (1) recurrent bacterial infections, or (2) infections with unusual organisms.

Question 4

Draw the graph showing changes in serum antibodies of an individual from fetal -> 1 year.

When do congenital immunodeficiencies become evident?

Answer 4

Question 5

Describe the T cell subsets

Answer 5

Depending on CD4+ T helper cells are activated, it influences how they’re activated (how antigens are presented) we might generate a predominantly Th1 or Th2 population of T helper cells.

Th1 will result in upregulation of

• IgM, IgG
• Cytoxic T cells
• Acute virus and bacterial infections

Th2 will result in upregulation of

• IgG, IgE
• Mucosal immunity
• Chronic infections, especially parasites

Th17 will result in upregulation of

• Mucosal immunity
• Promote inflammatory processes

Treg will result in

• Down regulation of other classes

Question 6

Describe Checkpoint Regulators

Answer 6

Surface interactions that either upregulate or downregulate immunity.

• B7 with CD28 is important to turn on responsiveness (once the T cell recognises an antigen)
• B7-1 can also interact with CTLA-4 and downregulate responsiveness
• PD-1 and PD-L1/2 can also downregulatory checkpoint/inhibitory pathway

Some cancer cells avoid immune-detection by upregulating the inhibitory pathway.

Blocking these immune-inhibitory interactions it he role of immune checkpoint inhibitor drugs (e.g. for cancer)

Question 7

Describe the difference between Immune respinsiveness between primitive and modern humans

Answer 7

In primitive humans, there were a balance between Th1, Th2 and Treg (deal with parasites etc.)

Due to changes (lifestyle, antigens and changes in microbes in us), this has resulted in greater activation of Th17 (inflammatory) and less T(reg) cells. So we now see more overreactive immune responses (allergies and autoimmunity/inflammatory diseases)

Question 8

What are some antigen and antibody consideration and its effect on Immune responses

Answer 8

Antigen Considerations

• The nature of an antigen affects sort of responses, which can be generated against it.
  
  • Foreign antigens that are similar to self-antigens stimulate poor response.
  • _How an antigen is processed a_nd nature of HLA presentation structures will affect which epitopes are available for recognition by T and B lymphocytes.

Antibody Considerations

• Antibodies present in an individual at time of antigen exposure can:
  
  • Effectiveness of opsonisation affects response kinetics
    
    • Either enhance immune responses against antigen by opsonization;
    • Or diminish responses by leading to rapid antigen removal.
  • In addition, IgG and IgM antibodies respectively to exert inhibitory and enhancing effects on generation of antibody-forming cells (promoted by high IgM, diminished by high IgG)

Question 9

Describe the Neuroimmune Network

Answer 9

There are extensive interconnections between immune system and autonomic nervous system of sympathetic and parasympathetic nerves, and neuroendocrine system centred on the hypothalamus-pituitary-adrenal (HPA) axis.

• Nervous system senses physical world and maintains adequate relationship with it
• Immune system senses microbial world and maintains adequate relationship with it

There’s a large amount of connection between the neuro and immune network- largely by 3 pathways.

• Autonomic Nervous System
  
  • Particularly via secondary lymphoid organs
• Endocrine System
  
  • T and B cells are responsive to hormones
• Immune system
  
  • Immune cytokines also influence our nervous system and affect our physiology.
• Corticosteroids are immunosuppressive and depress a range of immune measures.
• Other hormones controlled by the hypothalamus-pituitary-adrenal axis also influence immune responsiveness in a variety of ways.
• Noradrenergic nerve fibres terminate in T cell areas of lymph nodes and altering the activity of these nerves can affect immune responsiveness.
• Electrochemical activity in the hypothalamus alters during the course of an immune response to antigenic challenge.
• A variety of neuroendocrine mediators are also produced by cells of the immune system.
• Certain cytokines also act in the nervous system.

Question 10

Describe the relationship between Pro-inflammatory Cytokines and the Nervous System

Answer 10

Pro-Inflammatory Cytokines and Nervous System (Illness Behaviours)

Pro-inflammatory cytokines, particularly IL-1, have role in psycho-neuro-immune connections:

• Increases body temperature.
• Increases slow wave sleep when administered to brain lateral ventricle.
• Promotes illness behaviours.
  
  • _​_Withdrawing etc.

I_L-1 is secreted by astrocytes and glial cells._

• Acts on vagus nerve branches. IL-1 is a neurotransmitter in p_re-optic and hypothalamic neurones._
• Immune responses can be modulated by psychological factors such as stress, anxiety, depression, coping and social support.
• Proinflammatory cytokines are involved in illness behaviours.
• Psychological factors (e.g. stress and anxiety) can diminish pro-inflammatory cytokine production and slow wound healing.
• Frequent correlations have been found among high perceived stress, poor coping, depressed immune responsiveness and increased susceptibility to infectious illnesses.

Question 11

Describe the relationship between ANS and the immune system

Answer 11

Histochemical staining techniques for identification of small nerves have revealed extensive innervation of all primary and secondary lymphoid organs by autonomic nerve fibres. It is _predominantly noradrenergic (sympatheti_c), therefore norepinephrine is predominant neurotransmitter.

In lymph nodes, these nerves appear to terminate predominantly in T cell-rich regions, suggestive of possible links to immunoregulatory functions.

• Surgical or chemical ablation of sympathetic nerves to lymph nodes or spleen augments antibody responses in these organs.
• Conversely, ablation of parasympathetic innervation of lymphoid tissues generally depresses immune responsiveness.

Density of these nerves related to social temperament. Psychosocial factors affect immune regulation.

• High sociability correlates with low sympathetic innervation of lymph nodes.
• Low sociability correlates with high sympathetic innervation of lymph nodes

Question 12

Describe Stress and the Immune System (Neuroimmune Connections)

Answer 12

A wide variety of immune measures have been found to be affected by stress (appreciate the extent, don’t learn specifics):

• Responses to vaccination
• Would healing
• Lymphocyte proliferatiion
• Development of antigen-specific cytotoxic T cells
• Generation of specific antibody responses
• Macrophage activation
• TH/Treg balance
• Secretion of cytokines
• Expression of cytokine receptors
• Trafficking patterns of immune cells around the body

Question 13

Describe the Influenza Vaccination research

Answer 13

• Elderly people caring for relatives with Alzheimer’s disease, compared with non-caregiver control group.
• Less antibody response for caregivers group 1 month after influenza vaccination.
• For controls, 70% had a good response to the vaccination
• For caregivers, only 40% had a good response to the vaccination
  
  • Perhaps the lifestyle (stress, sleep, food etc.) have influenced their response to the vaccine.