Module 6 - Lecture 4
Lecture 4: Immunology in Medicine
Overview of key themes in immunology relevant to medicine, including:
Infectious diseases
Immunodeficiency
Genetic deficiencies and AIDS
Autoimmunity and chronic inflammatory diseases
Allergies
Microbiome and western lifestyle diseases
Transplantation (not discussed here)
Cancer immunotherapy (not discussed here)
Immunodeficiency Diseases
Definition of immunodeficiency:
Immunodeficiency can be genetic or caused by exposure to chemical or biological agents, e.g., human immunodeficiency virus (HIV).
Stress can lower immune function.
Consequences of immunodeficiency:
Immunodeficient individuals are subject to recurring infections and cancer.
Genetic Deficiencies in the Acquired Immune System
Defects in B cell production/function lead to susceptibility to:
Extracellular bacterial infections
Gut viruses
Other infections may be cleared as T cell responses remain intact.
T cell deficiency is more severe than B cell deficiency due to:
T helper cells being necessary for most B cell activation and antibody production.
T cell deficiency results in “Severe Combined Immunodeficiency” (SCID).
Prevalence of SCID:
Approx. 1 in 100,000 births have SCID.
Untreated SCID patients typically die before the age of 1.
SCID Patients and Treatment
In the absence of treatment, SCID patients can only survive in a sterile environment.
Notable Case:
David, known as the “boy in the bubble,” was deficient in the enzyme adenosine deaminase (ADA).
He survived in a sterile bubble until age 12, when he had a failed bone marrow transplant from his sister.
Modern SCID Treatments:
Bone marrow transplant
Gene therapy
Administration of ADA enzyme for ADA deficiency.
Acquired Immunodeficiency Syndrome (AIDS)
Overview of HIV-1:
Human Immunodeficiency Virus-1 (HIV-1) is a retrovirus:
Contains an RNA genome which is reverse transcribed into double-stranded DNA.
This DNA integrates into the genome of infected cells.
Infection Process:
HIV-1 infects cells with the surface molecule CD4, including T helper cells.
Consequences of HIV-1 infection:
Leads to death of T helper cells, resulting in immunodeficiency and development of AIDS.
AIDS patients are vulnerable to various infections and cancers, such as:
Tuberculosis
Fungal pneumonia
Candida yeast infections
Current treatment for HIV:
HIV is now well controlled with drug treatment.
Autoimmunity
Definition of autoimmunity:
Occurs when the immune system attacks the body’s own tissues.
Mechanism of autoimmunity:
Tolerance involves the deletion or control of T and B cells that attack “self” molecules.
Failure of tolerance leads to autoimmunity, characterized by:
Attack on the body by T cells and antibodies.
Factors influencing autoimmunity:
Genetic factors
Environmental factors, e.g., infections providing “molecular mimicry.”
Foreign antigens may mimic self-proteins and promote autoimmune responses.
Excessive inflammation can promote responses against self-antigens.
Sex bias in autoimmunity:
Many (but not all) autoimmune conditions are more prevalent in women.
Women typically have better outcomes in many infectious diseases compared to men.
Types of autoimmunity:
Can be organ-specific or systemic (body-wide).
Specific Autoimmune Conditions
Type I Diabetes
Description:
An organ-specific autoimmune condition involving destruction of pancreatic islet β-cells responsible for insulin production.
Mechanism of pathology:
Cytotoxic T Lymphocytes (CTL) destroy β-cells leading to loss of insulin production.
This results in loss of control over blood glucose levels.
Specific antigens and immune cells involved:
Islet-specific T helper cells and CTLs recognize a variety of β-cell-specific antigens, including insulin itself.
Multiple Sclerosis
Description:
Affects nerves of the central nervous system, causing issues with sensation, movement, and vision.
Mechanism of pathology:
Myelin sheath surrounding nerve axons is attacked, disrupting transmission of nerve signals.
Epidemiological observations:
More common in Caucasian women living in Northern Europe than in tropical regions, suggesting a role for sunlight.
Sunlight is known to regulate immune responses.
All patients have Epstein Barr Virus (EBV) infection, which lives long-term in B cells.
The specific role of EBV in multiple sclerosis is not fully understood.
Immune responses involved in this disease:
Both T and B cell responses are important.
Narcolepsy
Description:
Characterized by excessive daytime sleepiness and sometimes sudden onset of sleep.
Mechanism of pathology:
Loss of neurons in the hypothalamus that produce hypocretin neuropeptide hormones regulating wakefulness.
This condition is thought to be due to a T cell-mediated autoimmune attack on neurons.
Epidemiological observations:
New cases tend to occur seasonally, about 5 months after flu season.
Linked to 2009 “swine flu” vaccinations in Scandinavia due to evidence suggesting molecular similarity between an influenza antigen and hypocretin protein.
Allergy
Definition:
Allergy is an inappropriate immune response to environmental or food molecules.
Allergens:
Environmental and food molecules that elicit allergic responses include pollen grains, house dust mites, peanuts, and bee venom.
Mechanism of allergy:
Involves a three-stage process:
Prior sensitization to allergen activates acquired immune responses, producing specific IgE antibodies.
Allergen binds to IgE on mast cells, leading to degranulation—release of histamine.
Histamine increases blood vessel permeability, causing symptoms of allergy such as swelling, smooth muscle contraction, and more.
Potential severe outcomes:
Severe allergic responses can lead to anaphylactic shock characterized by a dangerous drop in blood pressure.
Similarities between allergic responses and defense against parasitic worms:
IgE and mast cell responses are beneficial in expelling parasites and can cause increased mucus production.
Allergy Sensitization and Triggering Process
Antigen (allergen) invades body.
Plasma cells produce large amounts of class IgE antibodies against the allergen.
IgE antibodies attach to mast cells in body tissues and to circulating basophils.
Upon subsequent invasion by the same antigen:
Antigen combines with IgE attached to mast cells (and basophils).
This triggers degranulation and release of histamine and other chemicals.
Histamine causes:
Blood vessels to dilate and become leaky, promoting edema.
Stimulation of large amounts of mucus secretion.
Constriction of small respiratory passages (bronchioles), which can lead to asthma.
Incidence of Type I Diabetes
Reference:
Lancet Diabetes Endocrinol 2020; 8:226–38.
Differences in incidence of autoimmune conditions can be both genetic and environmental.
Changes within short time frames in one country must be due to environmental factors.
Question:
Why are allergies and autoimmunity increasing in developed nations?
Autoimmune conditions such as type I diabetes are increasing.
Moreover, asthma and allergies are recognized to have increased and to be much more prevalent in developed countries.
Epidemiological Studies
Findings indicate that lifestyle factors may promote allergies and autoimmunity.
Example:
Finland has one of the highest incidence rates of type I diabetes globally, while neighboring Karelia has significantly lower levels.
Populations in Finland and Karelia are genetically similar, but socio-economic and lifestyle differences exist.
Allergies, including pollen sensitivity and hay fever, are significantly higher in Finnish children compared to Karelian children.
Karelia is typically poorer and more rural, suggesting a correlation between lifestyle, modern living, and the prevalence of allergies and diabetes.
The Old Friends Hypothesis
Concept:
The human body is seen as an ecosystem with interdependence of commensal microbes and immune system development.
A 70 kg person may carry about bacteria, totaling around 0.2 kg—paralleling the cell count in the body.
Importance of microbial colonization in infants:
Babies benefit from early colonization by a diverse population of beneficial organisms.
Explanation of the Old Friends Hypothesis:
Humans co-evolved with various microbes that influence immune system development and regulation.
Encountering these organisms is crucial for normal immune function.
Role of helminths (worm parasites):
Helminths may regulate immune responses that also link to allergies.
In developed nations, decreased helminth burden is thought to correlate with increased allergy incidence.
Modern Lifestyle Factors Impacting the Microbiome
Factors that may alter microbiome include:
Caesarian birth and bottle-feeding.
Antibiotic use.
Increased household cleanliness and prevention of children from interacting with dirt.
Use of antibacterial products such as cleaning products and toothpaste (e.g., triclosan).
Urban and indoor lifestyles leading to reduced contact with nature and soil.
Exposure to traditional farms and animals appears protective against allergy.
Diet and obesity alter gut flora significantly.
Importance of dietary fiber:
Dietary fiber consists of complex carbohydrates resistant to digestion in the small intestine and is plentiful in traditional rural diets.
Traditional diets provide more than 50g of fiber/day; Western average is 15-20g.
Benefits of a high fiber diet:
Changes gut flora
Metabolized by beneficial colon bacteria into short-chain fatty acids (e.g., acetate, propionate, butyrate).
These fatty acids are anti-inflammatory and serve immune regulation.
Additional health benefits of dietary fiber:
Reduces cholesterol
Controls blood glucose
Decreases colon cancer risk
Summary and Recommendations
To promote a healthy microbiome and appropriate immune regulation, individuals are encouraged to:
Maintain exposure to diverse microorganisms (referred to as “good clean dirt”).
Consume high-fiber foods for optimal health benefits.
General advice: "Look after yourselves!"