Adaptive and Innate Immune Responses: A Comprehensive Guide, Study notes of Microbiology

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Microbiology Exam 3-

Unit 7:

Contrast innate and adaptive immune responses.

• VOCABULARY- First line of defense-Innate defenses that are designed to keep pathogens out Specificity- The ability of the adaptive immune response to recognize many different pathogens. Second line of defense- Innate defenses that work if a pathogen breaches first lines of defense Antigen- Any molecule that can initiate an immune response. Third line of defense- Adaptive defenses that work if both first and second lines fail to rid the body of the pathogen. Innate immunity- Non-specific defense mechanism, provides the first lines of defense, protects host from a wide range of potential pathogens. Adaptive immunity- Highly specific immune defenses against pathogens, induces memory cell formation, B-cells, antibodies, and T cells are all main players.

Innate vs Adaptive Immune Responses

Highly evolved species such as humans have both innate and adaptive immune responses that make up the immune system. Defenses in the innate immune response are always on providing constant surveillance against potential pathogens. Additionally, the innate immune system works to turn on adaptive immune responses which are typically stronger responses and generate memory cells B and T cells. The hallmark features of each system are listed down below.

Hallmark Features of the Innate Immune System:

• Always on
• Considered the first and second lines of defense
• Non-specific defenses
• Present at birth

Hallmark feature of the Adaptive Immune System:

• Slower to turn on/activate (about 7-14 days)
• Stronger response
• Considered the third line of defense

pathogens. Normal microbiota also works to keep us healthy by secreting chemicals such as bacteriocins to kill potential pathogens.

Mechanical Defenses

Mechanical defenses prevent pathogens from entering an organism or flushing them out quickly and are also classified as the first line of defense against pathogens. Mechanical defenses include:

• Tears - Eyelashes and eyelids work to prevent microbes from entering the eye. The flushing actions of tears protect the mucous membrane of the eyes by cleansing the surface of the eye if microbes enter there. In addition, tears contain lysozymes and IgA antibodies for further protection.
• Urination - Urine itself is usually sterile, but bacteria from the skin can enter the urethra and find their way to the bladder. Urination flushes out any bacteria that are in the bladder before they can attach and cause an infection.
• Coughing/sneezing - The act of coughing or sneezing propels pathogens out of the upper respiratory tract before an infection can develop.
• Shedding of Skin - As skin cells die, they shed in sheets taking any bacteria residing there with them.
• Stomach Acid - The acidic environment of the stomach will kill bacteria consumed in food. Only bacteria adapted to the acidic stomach can survive there.

Physical barriers prevent pathogens from entering an organism while mechanical defenses work to flush them out.

Second Lines of Defenses: Chemical Defenses

When pathogens do enter the body, the second line of the innate immune system responds with inflammation, pathogen engulfment, and secretion of immune factors and proteins.

Chemical defenses

Innate responses can be caused by a variety of cells, mediators, and antibacterial proteins. If the first line of defense is compromised, the second line of defense is activated. These defenses are made up of many nonspecific responses that defend against pathogens.

The following are examples of chemical defenses:

• Chemical and Enzymatic Mediators in body fluids
• Antimicrobial Peptides (AMPs)
• Acute-Phase Proteins
• The Complement System

Chemical and Enzymatic mediators

Fluids produced by the skin that act to interfere with microbial growth. The following are common examples of chemical and enzymatic mediators:

• Sebum
• Lysozyme
• Lactoferrin

Antimicrobial Peptides

Antimicrobial Peptides (AMPs) are a class of non-specific chemicals that are produced by the body. AMPs work to cause cell damage in microorganisms by damaging cell membranes, destroying nucleic acids (DNA/RNA), or interfering with macromolecule synthesis (such as the cell wall). The following are examples of antimicrobial peptides:

- Bacteriocins-

o Secreted by resident normal microbiota,

o Target: bacteria,

o Mechanism of action: disrupt membrane integrity.

- Defensins- o Secreted by epithelial cells, macrophages, and neutrophils o Target: bacteria, fungi, and many viruses o Mechanism of action: disrupt membrane integrity

Blood contains formed elements known as red blood cells (RBCs), platelets, and white blood cells (WBCs). White blood cells have an important role in the innate immune response.

White Blood Cells

White blood cells are nonspecific innate defenses against pathogens or antigens. White blood cells include:

1. Neutrophils
2. Eosinophils
3. Basophils
4. Monocytes (Macrophages)
5. Lymphocytes

Phagocytosis

Phagocytosis is an important and effective mechanism of destroying pathogens during innate immune responses. The main phagocytic cells of the immune system are as follows:

1. Macrophages
2. Neutrophils
3. Dendritic Cells

The process of phagocytosis includes 4 main steps:

1. Chemotaxis/Adhesion
2. Ingestion
3. Fusion
4. Digestion/Excretion

Antigen Presentation

Some of the phagocytes can act as antigen-presenting cells. Macrophages and dendritic cells can engulf the pathogen and process it, placing the antigen on their MHC class II receptor. B cells can also be antigen-presenting cells in some circumstances. The B cell processes the antigen differently.

Second Lines of Defense: Inflammation & Fever

Inflammation

Inflammation is part of a very basic form of immune response and typically carries a perceived negative effect, the inflammatory process is important for the recruitment of cellular defenses needed to eliminate pathogens.

Inflammation has four characteristics:

1. Heat
2. Redness
3. Pain
4. Swelling

Fever

Fever is a systemic sign of inflammation. Internal or external pyrogens cause the release of prostaglandin which stimulates the hypothalamus to reset the body's thermostat raising the body's temperature.

A fever works to enhance the innate immune defenses by stimulating leukocytes to kill pathogens. Additionally, a rise in body temperature helps to inhibit or slow down the growth of pathogens (mesophiles) who's optimal growing temperature is 37 degrees Celsius.

Benefits- A fever increases over all metabolism.

• increases cytokine activity
• stimulates leukocyte activity
• inhibits the growth of pathogens
• increases iron-binding proteins stealing iron from pathogens

Disadvantages- While most fevers are helpful there are drawbacks.

• Tachycardia
• Acidosis
• Dehydration

Superantigens can cause a fever to increase beyond what is helpful leading to organ damage, shock, and even death.

Once the barriers of the first lines of defense have been breached, the second line of defense mechanisms tries to rid the body of potential pathogens.

Adaptive Immunity-

Adaptive immunity is the third line of defense. It is specific and can remember thousands of antigens.

• Adaptive immunity is broken into humoral and cellular immunity. o Cellular immunity responses target intracellular pathogens as well as abnormal cells.

- Normal Flora- Microbial collection that consistently inhabits the bodies of healthy animals. - Septicemia- The presence of bacteria growing in the blood - Symbiosis- A relationship between two organisms - Antagonism- Opposed to something, in competition. - Host- An organism that provides a home for another organism - Pathogen- An organism that causes disease - Opportunistic Pathogen- An organism that causes disease when the host is immunocompromised, or it finds its way to the wrong location

Normal microbiota- refers to the microorganisms (bacteria, fungi, and archaea) that

reside on the skin, in saliva, oral mucosa, conjunctiva, gastrointestinal, and urogenital tracts. Normal microbiota plays an important role in the first line of defense against invading pathogens.

Hosts benefit from normal microbiota in the following ways:

• Occupation of binding sites on host cells
• Competition for nutrients
• Secretion of helpful substance such as bactericidins and vitamins

Normal microbiota is an important host innate immune defense.

Advantages and disadvantages of normal microbiota-

• Advantages- o Prevent the growth of pathogens by competing for nutrients and space o Produce growth factors, such as folic acid and vitamin K o Produce chemicals that inhibit the growth of other organisms. o Prevent pathogens from attaching to our cells o Stimulate the immune system
• Disadvantages- o Normal microbiota can cause disease if they breach the surfaces they colonize and gain access to the circulation or deeper tissues.

Locations of Normal Microbiota-

• Conjunctiva- The number and species of the normal microbiota of the conjunctiva is not well documented. The microbes that are present defend against known pathogens.

• Brain- The brain and central nervous system are sterile. The blood brain barrier protects the brain from the blood and lymphatic system keeping out most potential pathogens. If pathogens do breech, meningitis or encephalitis are the result.
• Oral Cavity- There are many different species of bacteria and archaea in the oral cavity. Saliva contains lysozymes that can help fight them and prevent them from being pathogenic. Streptococcus mutants is one such microbe that resides in the mouth but can ferment sugar to cause tooth decay (caries). Another organism commonly found in the oral cavity is Candida. Just like in the vagina, a disruption in normal microbiota can make candida over grow causing oral thrush.
• Skin- The normal microbiota of skin produces antimicrobial substances and out competes other microbes that land on the surface of the skin. Common species found are Staphylococcus, Corynebacterium, and Propionibacterium.
• Blood and Lymph- Blood should be sterile. The presence of bacteria in the blood indicate septicemia or bacteremia. Pathogens can enter the blood through open wounds or spread from other sites of infection. Lymph is usually sterile, but if there is an infection, pathogens are often detected in the lymph as the immune system is fighting off the pathogens.
• Gastrointestinal Tracts- The small and large intestine have a vast population of normal microbiota. These bacterial populations decrease the hance of infections by pathogens, help digest fiber and cellulose, and make vitamins for our absorption. There are many species of bacteria, archaea, and fungi found in the GI tract.
• Kidney- The kidney and ureter and bladder are technically sterile environments. However, normal microbiota from the skin or the large intestine can find their way into the bladder and potentially cause an infection in the bladder (cystitis) or even climb into the kidney causing pyelonephritis or glomerular nephritis. Bacteria in the blood can also find their way into the kidney.
• Vagina- Microbiota in the vagina compete with opportunistic pathogens, like the yeast Candida, which prevents infections by limiting the availability of nutrients therefore inhibiting the growth of Candida, keeping its population in check. There are species of Lactobacillus and occasionally protozoa as well.

Note: Typically, the brain, meninges, and blood are sterile and should be free

from microbes, even normal microbiota. The identification of

microorganisms in these areas signals a significant infection.

• Conjunctiva Transcript- Conjunctiva has many different microbes that live there. The species and number are not well documented according to the textbook by Parker, but they do know that there are some there. What they do in the conjunctiva they're not completely certain of, but we know that there are some there that can inhibit the growth of pathogens and compete for nutrients in space.
• Brain Transcript- The brain has a blood-brain barrier in it and that prevents the passage of microbes to the nervous system or the nervous tissue. Brain should therefore be sterile. Should bacteria viruses or fungus enter the brain tissue Meningitis or Encephalitis will be the result. The brain environment is tightly controlled by the blood-brain barrier and we really don't want to see any normal microbiota there.

other bacteria disrupting the normal numbers and when this happens a bacterial infection of the vagina can result.

Types of Symbiosis-

Symbiosis is any relationship between two or more biological species. Types of symbiosis are categorized by the degree to which each species benefits from the interaction.

There are four types of relationships between prokaryotic cells and their host.

• Mutualism- A symbiotic relationship where both organisms benefit is called a mutualistic relationship. An example is the normal microbiota in the intestines which aid in digestion and absorption of vitamins while the human provides fiber for food and a place for those bacteria to live.
• Commensalism- In commensalism, one organism is unaffected and the second organism benefits. An example is the normal microbiota that live on our skin. They have a place to live and use our dead skin cells and oils for food, but we are not harmed or benefited in any way. Occasionally these could be opportunistic pathogens.
• Parasitism- In a parasitic relationship, one organism benefits at the expense of another. Most pathogens are parasites. Parasites are provided with food and a place to live while the host is harmed by becoming ill.
• Neutralism- A symbiotic relationship where neither organism is harmed or benefited in any way is a neutral relationship. Both organisms coexist with no affects.

Compare a cell mediated versus humoral response.

There are two main mechanisms of immunity within the adaptive immune system – humoral and cellular.

Vocabulary

• Antigen- A abnormal proteins or other substance that can cause an immune response
• Opsonization- Coating of bacterium or other pathogen with antibodies or complement proteins enhancing phagocytosis
• Epitope- The part of an antigen that an antibody can bind to

• Proliferation- A rapid increase in cell umber by mitosis
• Hapten- A free epitope or small molecule that can cause an immune response when bound to a larger protein Ex: detergents
• Differentiation- The process of becoming different cell lines example: T helper 1 vs T helper 2 or B cell to plasma cells
• Cytokine- Chemical messenger

Antigens

Activation of the adaptive immune response is triggered by pathogen-specific molecular structures called antigens and are specific to each pathogen. The term antigen is a combination of antibody and generator.

There are antigens on ALL pathogens and these antigens plan an important role in both the humoral and cell-mediated responses.

Examples of Common Antigens

• Capsules
• Cell Walls
• Fimbriae/Flagella/Pili
• Toxins
• Secreted enzymes
• Viral capsids/envelopes/spikes

Antigen Presentation

• Some of the phagocytes can act as antigen-presenting cells. Macrophages and dendritic cells can engulf the pathogen and process it, placing the antigen on their MHC class II receptor. B cells can also be antigen-presenting cells in some circumstances. The B cell processes the antigen differently.

T Cell-independent B cell Activation

• If an antigen has a repeating epitope pattern that can bind to a B cell, it can stimulate the B cell to differentiate without help from Helper T cells. More than one B cell receptor can bind to the same epitope (also called cross-linkage) producing a second signal for the B cell to differentiate and divide eventually becoming plasma cells and secreting antibodies.
• These responses are weaker than a T cell-dependent antigen (discussed below) and do not produce memory B cells.

Humoral Immunity

Humoral immunity involves antigens from pathogens that are freely circulating, or outside the infected cells. Humoral immunity refers to mechanisms of the adaptive immune defenses that are mediated by antibodies secreted by B lymphocytes, or B cells. Antibodies produced by the B cells will bind to antigens, neutralizing them, or causing lysis or phagocytosis. The major components of the humoral response are:

• B-cells
• T helper cells/Cytokines
• Antibodies
• Plasma Cells

The B-Cell

• B lymphocytes originate and mature in the bone marrow
• B cells will travel to the spleen and immune organs where they continue to mature and reside
• Produce and secrete immunoglobulins (antibodies)
• Can act as an antigen-presenting cell (APC)

T Helper Cells

• T cells sometimes play an important role in the activation of B cells. The helper T cell works to activate B cells by acting as a secondary binding signal and by secreting cytokines to induce isotype switching by the B cell.

Primary and Secondary responses

• The primary immune response occurs when an antigen comes in contact with the immune system for the first time. During this time, the immune system has to learn to recognize antigen and how to make an antibody against it and eventually produce memory lymphocytes.
• The secondary immune response occurs when the second time the person is exposed to the same antigen. At this point, the immune system can start making antibodies immediately. Additionally, the secondary response is strong and more rapid than the primary response.

Antibodies

• Antibodies are glycoproteins that are found in bodily fluids and can be bound to the surface of B-cells.
• Move through the information below to learn more about antibodies including structure and function.

Antibody structure

Each antibody has two major parts, a constant region, and a variable region.

• The constant region (Fc region) identifies which of the 5 classes the antibody is in.
• The variable region is different for each antigen the body has been exposed to.

Antibody Functions

Antibodies play important roles in protecting the body against pathogens. Below are the antigen-antibody interactions that play a role in humoral immunity.

• Neutralization
• Precipitation
• Activation of Complement
• Opsonization
• Agglutination
• Antibody-dependent cell-mediated cytotoxicity (ADCC)

Antibody Classes

There are 5 antibody classes or isotype. The class of the antibody is determined by the constant region of the antibody molecule.

The 5 antibody classes are as follows:

1. IgG
2. IgM
3. IgA
4. IgD
5. IgE

The table below explains the three main types of T cells active and their function in a cell- mediated immune response.

T cell type CD molecule Activation Function

Helper T cell CD- 4 MHC Class II on Antigen presenting cells (APCs)

Activate B cells and stimulate humoral and cellular immunity.

Help activate macrophages and NK cells

Cytotoxic T cell CD- 8 MHC Class I on infected cells or APCs

Target cells infected with a virus or other intracellular pathogen. Regulatory T cell CD- 4 MHC Class II on APCs

Prevent autoimmune responses and involved in peripheral tolerance to self- tissues.

Helper T cell activation

Helper T cells are activated only by APCs and the MHC class II. The CD4 molecule on the Helper T cell must bind to the MHC Class II and at the same time recognize the antigen. Once activated cytokines from both cells will activate the Helper T cell and cause proliferation and differentiation into different cell lines. The overall effect is:

1. Secrete cytokines to increase the activity of cytotoxic T cells and innate phagocytes and NK cells.
2. Stimulate B cell differentiation and antibody production.
3. Stimulate immunity in general by increase the activity of phagocytic cells.

Note: Helper T cells are an important link between innate and

adaptive immune responses.

Cytotoxic T cell activation

T Lymphocytes are activated differently and are better at finding intra-cellular pathogens. Cytotoxic T cells recognize antigens on MHC Class I molecules. Cytokines secreted by APCs and helper T cells are involved in the proliferation and differentiation of cytotoxic T cells. Once activated cytotoxic T cells will secrete two proteins.

1. Perforin produces a hole in the target cell membrane.
2. Granzymes enter the target cell and cause apoptosis of the target cell.

Other cells involved in cellular immunity

In addition to Cytotoxic T cells, there are innate immune cells that act in cellular immunity.

Macrophages- Macrophages engulf and destroy bacteria or infected body cells. As an APC, macrophages can stimulate T cells. Natural Killer (NK) cells- Non-specific lymphocytes that can find and rid the body of virally infected host cells and cancer cells.

Compare Humoral vs Cell-mediated

Responses

Humoral vs Cell-mediated Responses

Humoral Responses

Immune response that mainly targets extracellular pathogens. Antibodies coat pathogen

to neutralize or target for phagocytosis.

• B-cells/Memory cells o Plasma cells
• Antibodies
• Antigen-Presenting cells
• T Helper cells

Cell-mediated Responses

Immune response that targets intracellular pathogens. Targets infected cells for cellular

death (apoptosis).