Title: The War Within: Immune Disorders and Autoimmunity

Authors: Jina Kum (Author)
Licence: CC BY-NC-SA 4.0

Immune Disorders

The War Within:

IMMUNE DISORDERS

Funded by the Government of Ontario.
The views expressed in this publication are the views of the author(s) and do not necessarily reflect those of the Government of Ontario or the Ontario Online Learning Consortium.

Overview

Click on the audio button for narration.

OVERVIEW

- The Immune System
  - Innate & Adaptive Immunity
- Immune Disorders
- Types of Hypersensitivity Disorders
  - Type I: Anaphylactic
  - Type II: Antibody-mediated
  - Type III: Immune complexes
  - Type IV: Cell-mediated
- Case Study: Maria Albu

The Immune System

The immune system is a collection of mechanisms that protect against disease by recognizing and eliminating pathogens, tumour cells, and microbial toxins.

Pathogens include:

Mycobacteria differ from other bacteria in terms of their cell wall structure and metabolism in that they require specific diagnostic tests to identify them.

Immune System Features

The immune system can be divided into two major arms: innate and adaptive immunity.

INNATE IMMUNITY

ADAPTIVE IMMUNITY

Activation does not require previous exposure to an offending agent (antigen); always ready to attack

Activation requires previous exposure to an antigen; protects against microbes that have evaded innate defenses

Exposure leads to immediate, maximal response

Delay between exposure and maximal response

Limited recognition of pathogens (predetermined by genome)

Unlimited recognition of pathogens (infinitely variable)

Exposure leads to immunological memory

Immunological memory: The body can remember an antigen after its first exposure (primary immune response). So, when the body is exposed to the same antigen again, it can mount an accelerated reaction, known as the secondary immune response. The secondary immune response bypasses several initial steps which were necessary to occur for the primary immune response. Immunological memory provides lasting immunity against infections.

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Components of Innate Immunity

[Image: Cross-section of skin layers]

Surface barriers (e.g., skin - Figure 1)

Cells

- Phagocytes: Neutrophils, monocytes/macrophages phagocytose, engulfing and digesting microbes and cell debris recognized by pattern-recognition receptors (Figure 2).
- Granulocytes: Eosinophils, basophils, and mast cells secrete chemical mediators to regulate the inflammatory response.
- Natural killer cells kill damaged/abnormal cells.
- Dendritic cells present antigens to initiate T cell responses.

Humoral (occurring in extracellular fluid) and chemical barriers

- Cytokines are released from injured cells and stimulate inflammation.

Figure 1: Illustration of the skin layers. The epidermis of the skin forms a surface barrier to protect our bodies from environmental pathogens.

Bacterium

Figure 2: Illustration of phagocytes engulfing a bacterium.

Components of Adaptive Immunity

Cell-mediated

- Lymphocytes: T cells, B cells, and natural killer (NK) cells
- Antigen-presenting cells and phagocytes: Dendritic cells and macrophages

Humoral

- Circulating antibodies

Antibodies (also known as immunoglobulins, or Ig) are produced by plasma cells (differentiated B cells) and bind to specific antigens to neutralize microbes and injured cells or target them for attack by other immune cells.

KEY FEATURES

- Recognition of specific non-self antigens
- Development of immunological memory (memory cells can be recruited to quickly eliminate a pathogen upon repeat infection)

Immune Disorders

Hypofunction refers to abnormally diminished function, while hyperfunction refers to excessive activity or function of the immune system.

Immune disorders can be broadly classified as either diseases of hypofunction or hyperfunction.

Hypofunction of the immune system can lead to increased susceptibility to infections and cancer.

Hyperfunction of the immune system, also known as hypersensitivity, leads to damage to normal tissues.

Diseases resulting from hypersensitivity are often chronic due to the persistence of these antigens amplifying the immune response (recall immunological memory).

Photo by Polina Tankilevitch (Pexels, a Canva Germany GmbH). See URL.

Hypersensitivity Reactions - Type I

Hypersensitivity Reactions

TYPE I: ANAPHYLACTIC

- Allergic (or atopic) reactions
- Exaggerated IgE-mediated immune responses against normally nonpathogenic antigens
- When IgE molecules on mast cells bind to antigens, mast cells become activated and degranulate
  - Releases histamine, which increases vascular permeability (leakiness) and mediates an inflammatory response
- Potentially fatal (i.e., anaphylaxis)
- E.g., Severe allergy to a bee sting that causes rapid swelling and breathing difficulties

Figure 3: Mast cells contain granules of histamine, which are released upon antigen interaction.
Courtesy of Ramya Gadde, M.D. and PathologyOutlines.com, see URL.

Anaphylaxis is a severe, life-threatening allergic reaction.

Hypersensitivity Reactions - Type II

Hypersensitivity Reactions

TYPE II: ANTIBODY-MEDIATED

- Antibodies bind to antigens on the surface of cells or tissues, targeting them for destruction
- Mediated by IgM and IgG antibodies
- E.g., Autoimmune hemolytic anemia (A rare red blood cell disorder where antibodies are directed against a person's own red blood cells leading to anemia)

Hypersensitivity Reactions - Type III

Hypersensitivity Reactions

TYPE III: IMMUNE COMPLEXES

- Antibodies bind antigens to form excessive amounts of circulating immune complexes
- Immune complexes become trapped in various tissues, which causes injury by activating innate immune mechanisms and neutrophilic-mediated inflammation
- E.g., Glomerulonephritis (inflammation and damage to the blood-filtering vessels of the kidney) resulting from the lodging of immune complexes in renal capillaries

Hypersensitivity Reactions - Type IV

Hypersensitivity Reactions

TYPE IV: CELL-MEDIATED (two types)

Delayed-type hypersensitivity, mediated by CD4+ T cells

- CD4+ T cells differentiate into helper T cells upon exposure to antigen via antigen-presenting cells
- Upon subsequent antigen exposure, differentiated helper T cells migrate to the site of exposure, activating macrophages (inducing phagocytosis) and neutrophils (inciting acute inflammation), resulting in tissue damage
- E.g., Contact dermatitis (inflammation of the skin) triggered by exposure to poison ivy

T cell-mediated cytotoxicity, mediated by CD8+ T cells

- CD8+ T cells destroy cells expressing a particular antigen
- E.g., Type 1 diabetes

Case Study

Maria Albu, a 22-year-old college student, presents with a persistent rash on her skin and complains of recurrent respiratory infections.

She reports a family history of autoimmune disorders. Maria is otherwise healthy and has no significant medical history.

Photo by Polina Tankilevitch (Pexels, a Canva Germany GmbH). See URL.

Case Study - Initial Examination

Initial Examination

Maria's vital signs are within normal range

Decreased level of immunoglobulin A (IgA)

High number of eosinophils

Eosinophils are identifiable by bi-lobed nuclei and large red (eosinophilic) granules, similar in colour to RBCs.

Figure 4: Peripheral blood smear showing a high number of eosinophils.
Courtesy of Lynh Nguyen, M.D. and PathologyOutlines.com, see URL.

Case Study - Clinical Evaluation

Clinical Evaluation

A skin biopsy is performed to examine the histological changes in the persistent rash. The analysis revealed:

- Subepidermal blistering (blistering below the top layer of the skin, i.e., the epidermis)
- Infiltration of neutrophils (involved in acute inflammation)
- Linear deposits of IgA along the basement membrane, consistent with dermatitis herpetiformis (Figure 5), a skin manifestation associated with celiac disease

Celiac disease is an autoimmune disorder characterized by immune reactions triggered by eating gluten. Gluten is a protein found in food containing wheat, barley or rye.

Figure 5: Clinical presentation of dermatitis herpetiformis.
Figure from Antiga, E. et al. Dermatitis Herpetiformis: Novel Perspectives. Front Immunol 10, 1290 (2019). https://doi.org/10.3389/fimmu.2019.01290

Case Study - Histological Analysis

Histological Analysis

A

B

The perilesional skin (the skin next to the blister, also known as the lesion) contains micro-abscesses of neutrophils in the dermal papillae. An abscess is a buildup of pus—a whitish fluid that contains many dead white blood cells, including neutrophils. Dermal papillae (boxed region) are fingerlike projections of the dermis that protrude into the epidermal layer of the skin. The neutrophilic micro-abscesses seen in dermatitis herpetiformis are the result of an immune reaction.

A subepidermal blister is a fluid-filled space formed between the upper skin layers in response to injury. One can see many neutrophils and eosinophils scattered throughout.

Figure 6: Histology of a subepidermal blister (A) and neutrophilic inflammation (B) in the skin, which are characteristic of dermatitis herpetiformis.
Courtesy of Michael Occidental, M.D., Randie H. Kim, M.D., Ph.D., and PathologyOutlines.com, see URL.

Case Study - Clinical Findings

Clinical Findings

HUMORAL IMMUNITY

Maria's blood test indicates a deficiency in IgA, a crucial component of humoral immunity (immune responses involving antibodies in body fluids). This could explain her recurrent respiratory infections as IgA plays a significant role in protecting mucosal epithelia, such as that of the lungs, from pathogens.

CELL-MEDIATED IMMUNITY

Histopathological examination of the skin biopsy revealed a T cell infiltrate in the dermal-epidermal junction, suggesting immune dysregulation.

Case Study - Hypersensitivities

Hypersensitivities

Click through the following cards to learn more about Maria's condition.

Hypersensitivities

Q: TYPE I: ANAPHYLACTIC
A: Maria is found to have an elevated IgE level, suggesting a Type I hypersensitivity disorder. Further analysis of the skin biopsy reveals mast cell degranulation, contributing to the persistent rash. Additional allergy testing is ordered to pinpoint the offending agent.

Q: TYPE II: ANTIBODY- MEDIATED
A: Autoantibodies (antibodies against self-antigens) targeting specific cells/tissues are identified, suggesting a Type II hypersensitivity reaction. Genetic testing reveals a predisposition to autoimmune disorders.

Q: TYPE III: IMMUNE COMPLEXES
A: Genetic testing reveals no predisposition to Type III hypersensitivity involving immune complexes, such as systemic lupus erythematosus (SLE). SLE is an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage.

Q: TYPE IV: CELL-MEDIATED
A: Maria suffers from celiac disease, which is a delayed Type IV hypersensitivity disorder. Her symptoms develop 48-72 hours after ingesting gluten, which contrasts IgE-mediated food allergies (Type I hypersensitivity) where symptoms develop almost immediately.

Knowledge Check

Innate Immunity MCQ

Q: Which of the following cell types in NOT considered part of innate immunity?
- A. Neutrophils
- B. Natural killer cells
- C. Macrophages
- D. T lymphocytes (correct)
- E. Mast cells

Knowledge Check

Adaptive Immunity MCQ

Q: Which of the following features distinguishes adaptive immunity from innate immunity?
- A. Lack of antigen specificity
- B. Instantaneous maximal response against a particular pathogen upon first exposure
- C. Faster immune response upon second exposure to a particular pathogen (correct) (The correct answer is C. A faster immune response upon second exposure to a particular pathogen describes immunological memory, which is exclusive to adaptive immunity. By contrast, innate immunity shows an instantaneous maximal (but non-specific) response regardless of the type of pathogen or the number of previous exposures to said pathogen. Innate immunity demonstrates lack of antigen specificity and use of pattern-recognition receptors, whereas adaptive immunity does not. Both innate and adaptive immunity features involvement of natural killer cells, macrophages, and dendritic cells, and therefore cannot be used to distinguish between the two.) (if not chosen: The correct answer is C. A faster immune response upon second exposure to a particular pathogen describes immunological memory, which is exclusive to adaptive immunity. By contrast, innate immunity shows an instantaneous maximal (but non-specific) response regardless of the type of pathogen or the number of previous exposures to said pathogen. Innate immunity demonstrates lack of antigen specificity and use of pattern-recognition receptors, whereas adaptive immunity does not. Both innate and adaptive immunity features involvement of natural killer cells, macrophages, and dendritic cells, and therefore cannot be used to distinguish between the two.)
- D. Involvement of natural killer cells, macrophages, and dendritic cells
- E. Use of pattern-recognition receptors

Knowledge Check

Type of Hypersensitivity MCQ

Q: A patient suffering from systemic lupus erythematosus receives an organ transplant to treat kidney failure associated with the disease. After surgery, the patient's cytotoxic T cells are activated by the donor's antigens, causing them to attack the transplanted kidney. How would you classify the hypersensitivity after transplantation?
- A. Type I: Anaphylaxis
- B. Type II: Antibody-Mediated
- C. Type III: Immune Complexes
- D. Type IV: Cell-Mediated (correct) (The correct answer is D: type IV (cell-mediated) hypersensitivity. This is because T cells are the major players in this immune reaction, leading to damage of normal tissue (i.e., hypersensitivity). Note: Systemic lupus erythematosus itself is an example of a type III hypersensitivity, but solid-organ transplant rejection described in this question is best classified as a type IV hypersensitivity because of T cell involvement.) (if not chosen: The correct answer is D: type IV (cell-mediated) hypersensitivity. This is because T cells are the major players in this immune reaction, leading to damage of normal tissue (i.e., hypersensitivity). Note: Systemic lupus erythematosus itself is an example of a type III hypersensitivity, but solid-organ transplant rejection described in this question is best classified as a type IV hypersensitivity because of T cell involvement.)

Knowledge Check

Immunoglobulin MCQ

Q: Further clinical testing determines that Maria is allergic to peanuts. Which class of antibody mediates this hypersensitivity reaction?
- A. IgA
- B. IgD
- C. IgE (correct) (The correct answer is C: IgE. This is because typical food allergies and sensitivities (with the exception of celiac disease) are classified as type I (anaphylactic) hypersensitivities, which are mediated by an exaggerated IgE response. Although this is not a type II (or so-called "antibody-mediated") hypersensitivity, IgE antibodies are still very important players in propagating inflammation.) (if not chosen: The correct answer is C: IgE. This is because typical food allergies and sensitivities (with the exception of celiac disease) are classified as type I (anaphylactic) hypersensitivities, which are mediated by an exaggerated IgE response. Although this is not a type II (or so-called "antibody-mediated") hypersensitivity, IgE antibodies are still very important players in propagating inflammation.)
- D. IgG, IgM
- E. This reaction does not involve antibodies