4.1 Immunity

4. Immunity

// 4. Immunity

07.07.21 | 20:13 tags:


This is a comprehensive mix with Microbiology’s Immunology Section. For Pathology specific notes, go to:

Immunity is divided into

  • Innante
    • Non-specific
    • No memory (amnesic)
  • Adaptive
    • specific
    • Memory (a-amnesic)

Innate Immunity

Innate immunity is the inborn resistance against infections that an individual possesses right from the birth, due to his genetic or constitutional makeup.

[[Pasted image 20210710171717.png]]

  • Barriers

    • Anatomical [skin]
    • Physiological [body temperature, pH, secretions and their contents]
      • Spermine in semen prevents gram-positive bacterial growth
  • Proteins

    • C-reactive proteins
    • Lectin
      • e.g: Mannose Binding Lectins [CD14 of macrophage recognizes]
    • Complement proteins
    • Surfactants and plasma proteins
    • Cytokines
  • Cells

    • Neutrophils

    • Macrophages

    • NK Cells

      • Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells, coming from a common progenitor. However, as cells of the innate immune system, NK cells are classified as group I Innate Lymphocytes (ILCs) and respond quickly to a wide variety of pathological challenges.
      • They kill virus infected cells
      • Kills tumor cells
    • Several rare types of lymphocytes that share the features of both acquired and innate immunity

      [[Pasted image 20210710182536.png]]

    • γδ T cells

      • Also called intraepithelial lymphocytes: They are present in epithelial lining of skin and mucosa
    • NK-T cells:

      • They are present in epithelium and lymphoid organs
    • B-1 cells:

      • They are found mostly in the peritoneal cavity and mucosal tissues
    • Marginal-zone B cells:

      • They are present at the edges of lymphoid follicles of spleen.
    • Mast Cells

      • They are present in the epithelial lining of the respiratory and other mucosa.
    • Dendritic Cells

      • They respond to microbes by producing numerous cytokines that initiate inflammation.
      • They also act as APCs - Antigen Presenting Cells
  • Normal Resident Flora

    • Normal resident flora lining intestinal, respiratory and genital tract exert several antimicrobial activities.
      • They compete with the pathogens for nutrition
      • They produce antibacterial substances.

[[Pasted image 20210710171444.png]]

BridgeFunction in InnateFunction in Acquired
Macrophages and Dendritic CellsInflammatoryAPCs
NK cells, neutrophils, eosinophilsInflammatoryADCC 1
Complement proteinsActivation of ComplementActivation of Classical Complement
CytokinesActivation of AdaptiveActivation of Innate
e.g:IL-1 activates T-helper cellIFN-gamma activation of macrophage -> epitheloid histocyte

How are pathogens recognized?

Pattern Recognition receptors

  • Bacteria/microbes exhibit patterns of conserved molecules common to most pathogens:
    • Pathogen/Microbe Associated Molecular Patterns
      • e.g: peptidoglycan, lipopolysaccharides (LPS), teichoic acid and lipoproteins present on bacterial surface.
  • Inflammation
    • Damage Associated Molecular Patterns

Pattern Recognition Molecules present on surface of host cells (e.g. phagocytes) that recognize PAMPs/MAMPs.

Types:

  • Toll-like receptor - main receptor for innate immunity

    • Causes activation of
      • NF-κB(Nuclear factor kappa-light-chain-enhancer of activated B cell - a transcription factor)
        • Causes recruitment of leukocytes
        • Activates COX-2
      • IFN-1 (type 1)
        • Antiviral action
    • Signals generated following binding of TLRs to MAMPs activate transcription factors that stimulate expression of genes encoding cytokines and enzymes, which are involved in several antimicrobial activities of cells of innate immunity.
  • C-type LR (Lectin Receptor)

    • Important against fungal infections

Cytosolic Receptors

  • RIG-like receptor
    • Act against viral nucleic acids
  • NOD-like receptor
    • Identifies:
      • Bacteria
      • K+ levels (eflux)
      • Uric Acid
      • ROS
    • Activates inflammasome
      • Which activates Caspase 1 -> IL1 -> Fever Inflammation

NK-Cells

This is a component of Innate Immunity

Hematopoitic Stem Cells -> Lymphoid Stem Cells

  • Lymphoid Stem Cells then differentiates
    • In Thymus gland: T cell
    • In Bone Marrow: B-Cell
    • Naive: Natural Killer Cells
      • Innate Lymphoid Cells

NK-Cells

  • They can secrete cytokines like T-cells
  • They do not have TCR
  • They were earlier known as Large Granular Lymphocytes [LGL]
  • They kill virus infected cells
  • Kills tumor cells

[[Pasted image 20210708230309.png]]

Two important receptors

  • Stimulatory/Activating receptor
  • Inhibitory Receptor
    • All cells in the body have MHC Class I molecule
    • This stimulates the inhibitory receptor
  • MHC class I has reduced expression in mutated cells (tumors) or viruses
  • Virus and cancer tumors have molecules that amplify molecules that activate the Activating receptor

NK cells also have

  • CD16
    • Also known as Fc receptor
    • Fc portion of the ImmunoglobulinG attaches to this
      • NK-cell destroys the coated antigenic cell
      • Antibody Dependent Cell Mediated Cytotoxicity [CDCC]
  • CD56

Adaptive Immunity

Acquired/Adaptive immunity is defined as the resistance against the infecting foreign substance that an individual acquires or adapts during the course of his life.

  • Specific
    • Developed through somatic recombination of gene segments
  • Memory (a-amnesic)
    • A proportion of T and B cells become memory cells following primary contact of the microbe, which play an important role when the microbe is encountered subsequently
  • Contributed by
    • T-cells - Cell-mediated
      • Effective against intracellular microbes
    • B-Cells - Humoral immunity
      • Effective against extracellular microbes
  • Response in days
  • Usually requires prior exposure
  • Diverse

Active Immunity

  • The host’s immune system is actively involved in response to the antigenic stimulus;
    • leading to the production of immunologically active T cells, B cells and production of specific antibodies
  • Active immunity may not even be protective at all
  • If infected by Haemophilus ducreyi, the patient may develop genital lesions following reinfection even while the primary infection is active.
  • Two types:
    • Natural Active Immunity

      • Develops from Natural exposure to microbial infection
    • Artificial Active Immunity

      • Develops following exposure to immunogen by vaccination
  • Active immunity often fails to develop when the host is immunocompromised
  • It is usually long lasting
    • Long: chickenpox, measles, smallpox, mumps and rubella
    • Short: following influenza virus infection
    • Premunition:
      • Lasts as long as the microbe is present
      • Seen in Plasmodium and spirochetes infection

Responses

[[Pasted image 20210710174938.png]]

[[Pasted image 20210710174914.png]]

Secondary Immune Response

  • When a subsequent antigenic exposure occurs
    • Latent period is either absent or of short duration.
      • This is because memory cells become active soon after the antigenic exposure
    • There may be a negative phase during which the antibody level may become lower than it was before the antigenic stimulus.
      • This is because the exposed antigen combines with the pre-existing antibody and thus the antibody level in serum falls down
    • Antibody surge: Secondary antibody response is prompt, powerful, long-lasting and mainly of IgG type.
      • Hence, it is said that, the booster doses of vaccines are more effective than the first dose.

Primary Immune Response

  • Active immunity develops only after a latent period following the antigenic exposure, which corresponds to the time required for the host’s immune apparatus to become active
  • Majority of activated T and B cells against the antigenic stimulus become effector T and B cells
    • Effector B cells include plasma cells.
    • Effector T-cells include Cytotoxic and Helper T cells
  • Minor proportion of stimulated T and B cells become memory cells, which are the key cells for secondary immune response
  • Effector B cells produce antibodies (mainly IgM type).
    • Antibodies appear in the serum in slow and sluggish manner;
    • reach peak
    • Maintain the level for a while and then fall down. Finally, a low titer of baseline antibodies may be maintained in the serum

Passive Immunity

[[Pasted image 20210710180403.png]]

Passive immunity is defined as the resistance that is transferred passively to a host in a “readymade” form without active participation of the host’s immune system

  • Again 2 types
    • Natural passive immunity
      • Involves the IgG antibody transfer from mother to fetus across the placenta
    • Artificial passive immunity
      • Develops following readymade transfer of commercially prepared immunoglobulin (e.g. Rabies immunoglobulin).
      • Another example is Adoptive Immunity
        • e.g: Injection of immunologically competent T-lymphocytes known as transfer factor. It is useful for treatment when the CMI is low, e.g. in lepromatous leprosy.

Important role in

  • Immunodeficient individuals (as host’s immune apparatus is not effective) and;
  • Post-exposure prophylaxis; when an immediate effect is warranted
  • It develops much faster relative to active
  • Amnesic immunity

B-cells

  • Located in the

    • Lymph node
    • Spleen
    • GIT
      • Mucosa Associated Lymphoid Tissue MALT
        • Present highly in the Peyer’s patches of the Ileum
      • Enteric fever is due to the ulceration of Peyer Patches and thus commonly it’s in the ileum
    • Tonsils
  • The lymph node has muliple zones

    • Cortex - B Cells
    • Paracortex - T-cells
    • Medulla Macrophages

[[Pasted image 20210707215520.png]]

B-Cell markers

CD stands for Cluster of Differentiation

  • CD 19 to 23 (1923)
    • CD19 - Pan B Marker (present in all stages of B-cell development)
    • CD21 - Receptor for EBV (Epstein Barr Virus)
  • CD 40
    • CD40 ligand is expressed on the T-cells
      • CD40L of T-cell and CD40
      • B-cell : T-cell interaction
      • Important in production of high quality antibody formation
  • CD80 / B7-1 CD86 / B7-2
    • CD80/86 are known as the B7 (B7-1 and B7-2 respectively)
      • These interact with CD28 on the T-cell to produce co-stimulatory signal

B-cells on activation -> Plasma-cell

  • Plasma cells secrete antibodies (immunoglobulins)

Immunoglobulins

Antibody or immunoglobulin is a specialized glycoprotein, produced from activated B cells (plasma cells) in response to an antigen, and is capable of combining with the antigen that triggered its production.

[[Pasted image 20210707220953.png]]

Made up of five classes of H chains and two classes of L chains:

  • Light Chains
    • λ (lambda)
    • κ (kappa)

Normal ratio : 3:1 to 3:2 κ:λ

  • Heavy Chains
    • α (alpha)
    • γ (gamma)
    • δ (delta)
    • ε (epsilon)
    • μ (mu)
  • All four H and L chains are bound to each other by disulfide bonds, and by noncovalent interactions, such as salt linkages, hydrogen bonds, and hydrophobic bonds.
  • Isotype
    • Different classes of antibodies in the same person
  • Allotype
    • Difference in antibody taken from two people
  • Idiotype
    • Variable part of antibody is different in same person

Regions

Each H and L chain comprises of two regions—variable and constant region, depending upon whether the amino acid sequences of the regions show variable or uniform pattern among different antibodies.

Variable Region

The first 110 amino acid residues near the amino terminal

  • These are dependent upon the first 110 amino acids near their amino terminal (NH3) of both L and H chains constitute the variable region—designated as VL and VH , respectively.
  • It represents antigen binding site of the antibody.
    • Hypervariable Region - zones with higher variablility
      • Form the antigen binding site, thus a.k.a - Complement Determining Region
      • Paratope: - a site on the hypervariable region/CDRs that makes actual contact with epitope

Immunoglobulin Classes / Isotypes

IgG

  • Presence of Gamma γ heavy chain
    • Maxiumum concentration
    • Crosses Placenta
    • Complement Activation
    • Opsonization
    • Subclasses
      • IG3 > IG1 > IG2 > IG4
        • Differ in their heavy chains - amino acids
      • IgG4 doesn’t fix complements while IgG2 has the poorest ability to cross placenta

IgA

  • Presence of the Alpha heavy chain
    • Forms:
      • Monomer in the Serum
      • Dimer in the Mucosa and Secretions - joined by J joining chain
        • Local or mucosal immunity
  • First Line of Defense (as majority of the infections have to pass through mucosal layer)
    • It activates the Alternate pathway rarely

Local or mucosal immunity is the immune response that is active at the mucosal surfaces such as intestinal or respiratory or genitourinary mucosa.

  • It is mediated by a type of IgA antibody called secretory IgA, which prevents the entry of microbes at the local site itself
  • Local immunity can only be induced by natural infection or by live vaccination (but not by killed vaccines)
    • Following administration of live oral polio vaccine (OPV);
    • Secretory IgA antibodies are synthesized and coated on intestinal mucosa which prevent subsequent poliovirus infections. Such immunity does not develop following injectable killed polio vaccine (IPV).

IgM

  • Presence of mu heavy chain
  • M for
    • Max Size
      • Pentameric
    • Max Molecular Weight
  • Complement Pathway Activation
    • Primary Immune Response - IgM is mostly produced than IgG (predominant)
      • In pentameric form, it has more paratopes for epitopes to bind to.
  • Monomeric form is present on B-Cell Receptor
  • Present only in intravascuar space due to weight
    • Thus provides immunity of the blood compartment

[[Pasted image 20210712030118.png]]

IgD

  • Presence of Delta Heavy Chain
  • Functions as acts as B-cell receptor

IgE

  • Presence of Epsilon Heavy Chain
  • Lowest Concentration
  • Attached to the surface of Mast Cells
    • Responsible for Type-1 Hypersensitivity Reaction
  • Heat labile antibody

Enzymatic Digestion

[[Pasted image 20210713201428.png]] Hinge region is sensitive for enzymatic digestion: the junction formed between CH1 and CH2 domain constitutes the hinge region

  • It is responsible for allowing the Ig molecule to assume different positions, thus helps the antibody reach towards the antigen
  • Papain digestion: cleaves above the disulphide of the bridge
    • Produces Two Fab fragments: Responsible for binding to antigen - Fab - fragment of antigen binding (soluble)
    • One Fc Fragment: Fragment of crystalized - an insoluble fragment that gets crystalized at lower temperatures
  • Pepsin digestion: cleaves below the disulphide of the hinge bridge
    • Produces F(ab)’ 2 fragments and digests Fc portion
  • Methocarpoethanol cleaves disulphide bonds only sparing the peptide bonds Note: IgE and IgM do not have hinge region - Instead they have an additional domain (CH4)

[[Pasted image 20210713203422.png]]

Monoclonal Antibodies

  • To-do

Antigens

Antigen is defined as any substance that satisfies two distinct immunologic properties—immunogenicity and antigenicity

Immunogenicity: It is the ability of an antigen to induce immune response in the body (both humoral and/or cell mediated)

  • Factors that affect it are
    • Size: Larger the better - more potent
    • Chemical nature: proteins are stronger than carbohydrates than lipids and nucleic acids -> P > C > L & N
    • Susceptibility to tissue enzymes
      • If the antigen/immunogen is susceptible to tissue enzymes -> antigen breaks down into multiple fragments generating more epitopes
      • Usually D-amino acid antigens are is not tissue enzyme degradable while L-amino acid antigens are
    • Structural complexity - more the number of amino acid and type and organization - more immonogenic
    • Foreigness - key factor
    • Genetic factor
      • Responders
      • Slow responders
      • Non-responders
    • Dose of antigen and frequency
    • Route of antigen administration
      • e.g: deltoid admin of Hep. B vaccine is better than gluteal
        • due to lesser number of APCs in gluteal fat
    • Antigen competition
      • When multiple antigens are administered, the response is not unbiased and it may be reduced or enhanced (such as in adjuvants)

[[Pasted image 20210712001032.png]]

[[Pasted image 20210711233927.png]] 2. Antigenicity: ability of antigen to combine with either of the above response or their secretions (antibodies)

All immunogens show antigenicity but the reverse is not true -e.g: haptens :::

EpitopeParatope
Part of AntigenPart of Antibody
Comprises of few (4/5) amino acids or monsachh. residuescorresponds to the epitope
  • In general, T-cells recognize sequential/linear epitopes
    • a single linear sequence of few amino acid residues
  • B-cells recognize conformational/non-sequential
    • formed by bringing together the surface residues from different sites of the peptide chain during its folding into tertiary structure

Haptens are low m.w molecules that lack immunogenicity (cannot induce immune response) but can retain antigenicity

  • Haptens may become immunogenic when combined with a larger protein molecule called carrier
  • Exogenous
  • Endogenous
  • Autogenous
Types of Antigens based on B-Cell activation
Non-Proteinaceous
Proteinaceous/T-Cell Dependent

[[Pasted image 20210712023340.png]]

Non-Proteinaceous Antigens / T-Independent

  • These are free antigens that do not require any additional cells for activation
    • Thus also known as thymic-independent antigens/T-cell independent
    • Pentameric IgM antibodies are produced when bound to monomeric form of IgM present on BCR
    • e.g: bacterial capsule, flagella and LPS (lipopolysaccharide)
  • Leads to T-cell indepent activation of B-Cell
    • They directly bind to immunoglobulin receptors present on B cells and stimulate B cells polyclonally.
    • It leads to increased secretion of non-specific antibodies (i.e. hypergammaglobulinemia).

[[Pasted image 20210707224227.png]]

Proteinaceous Antigens / T-Dependent

  • Requires the support of T-CeLLS for proper activation of Immune System

[[Pasted image 20210707224246.png]]

  • B-Cell or APCs (antigen presenting cells) expresses antigen on the surface
  • T-CR (T-cell receptor) then recognizes the antigen
  • T-cell then attaches to the MHC class
  • CD40(B-cell) and CD40L (T-Cell) interaction occurs
    • This leads to secretion of IL-4/IL-5
    • Cytokine Reference
    • This causes IgM -> IgG/A/E [isotype/class switching : change in heavy chain by IL-4/IL-5]
      • This is reaaallyy important for somatic hypermutation ^4e39b6
      • If this is cytokine secretion is blocked -> Hyper IgM syndrome

Superantigens

[[Pasted image 20210712024844.png]]

Superantigens are the third variety of biological class of antigens, recently described in the last decade. The unique feature of superantigens is,they can activate T cells directly without being processed by antigen-presenting cells (APCs).

  • They directly bridge MHC II and TCR
    • This non-specific activation of T-cells leads to massive release of cytokines - cytokine storm
      • Which include inflammatory mediators such as interferon γ, IL-1, IL-6, TNF-α, and TNF-β
    • This activates B cells polyclonally, which leads to increased secretion of non-specific antibodies
    • Important superantigens are staphylococcal and streptococcal toxins

[[Pasted image 20210712025038.png]]

T Cell

  • Named from the fact that they develop in the thymus
  • Present in the
    • Lymph Node

      • Paracortex

      [[Pasted image 20210707215520.png]]

    • Spleen

      • Periarteiloar Lymphoid Sheath
        • PALS
    • GIT

      • Present within the intraepithelial lymphocytes [IELs] |
      • Compare this with B cells in the Mucosal Lymph Node (MALTS)

Structure

  • T-cell Receptor (TCR)
    • Binds to prebound antigens only
    • Prebound antigens are presented by APCs
  • CD molecules
    • CD 1 to 5, 7 and 8 [CD1 CD2 CD3 CD4 CD5 CD7 CD8]
      • These are all T-cell markers
      • Pan-T-Cell Marker - CD3
        • Significant in signal transduction mechanism
        • Activation of T-cell assisted by calcineurin and IL-2
    • CD28
      • Costimulatory signal from APCs such as B-cells
      • Binds to Ce
    • CD40-L
      • Attaches to B-Cell CD40 receptor
      • Important for T-Cell B-Cell

T-Cells can be divided into:

  • CD4+ T Cells - Helper Cells
    • CD4 molecule is present

    • Subtypes

      T Cell typeReactionSecretion of
      Th1Type IV HRIL2 and IFN gamma
      Th2Type I HRIL-4 and IL-5
      Th17Responsible for Fungal infections and autoimmune disordersIL-17

  • CD+ T-cells - Cytotoxic
    • CD8 positive
    • Binds to MHC Class I

| CD4:CD8 | 2:1 | | —–– | — |

Activation of Immune System

  • Antigens are divided into
  • Proteinaceous antigens

    • T-Cell dependent
  • Carbohydrate/Lipid Antigens (non-proteinaceous)

    • T-Cell independent
  • Antigen presenting cells internalize antigens and process it

  • APCs then express the antigenic peptide through the MHC molecule

  • MHC molecule is responsible for attachment of antigenic peptide

  • Then APCs enter the systemic circulation and lymphatic circulation

  • Clonal Selection occurs:

    • Only a few T-cells come in contact with specific antigen peptides presented by the APC depending upon the specific antigen

T-cells:

  • Effector T-cells
    • Deals with the presentation
  • Memory T-cells
    • These remain dormant after developing antigen receptor
    • Deals with later infection
    • These are fewer in number
    • CD45RO is used to detect memory T-Cell
      • CD45 is present on leukocytes
      • Mem OR y - Memory device

APCs:

  • APCs internalize internal/external peptides (after being broken down)
  • The MHC chains produced by the Endoplasmic Reticulum is expressed on the APC surface along with the peptide in

Professional APCs

  • These APCs have a very high expression of MHC 2
  • Dendritic Cells

    • Langerhans cells (tissue resident macrophage) - Skin and Interstitial Cell
    • Follicular dendritic cells - reservoir for HIV present in - Lymph node and spleen
  • B-Cells

    • Activated B-cells turn into plasma cells -> secrete antibodies
  • Macrophages

    [[Pasted image 20210701093452.png]]

    • CD13, CD14, CD15 and CD33 are CD markers

Non-Professional APCs

  • These are non-standard APCs with low but significant expression of MHC
  • Fibroblasts
  • Endothelia Cells
  • Thymic epithelial cells
  • Glial Cells
  • Pancreatic Beta-Cells

MHC

Major Histocompaitibility Complex Also known as HLA - Human Leukocyte Antigen

  • The gene encoding is present on short arm of Chromosome 6p

[[Pasted image 20210713204137.png]]

  • Class I region codes for MHC I
    • MHC I is present in all nucleated cells (except sperms) and Platelets. Not present in RBCs.
  • Class II region encodes for MHC II
    • MHC II is present in all APCs
  • Class III region codes for
    • C2
    • C3 Convertase
    • C4
    • Properdin
    • Factor B
    • TNF-alpha and beta
    • 21-alpha hydroxylase
    • Heat Shock Protein
  • Cell Activated - immune cell activated
  • Ag Binding Cleft

MHC Class I

  • Made of 1 alpha chain - 3 alpha domains and ==1 beta chain ==
  • Antigenic cleft is present in between alpha 1 and alpha 2
  • Alpha 1 and alpha 2 are distal alpha domains
  • Alpha 3 is proximal alpha domain

Distal domains form the antigen binding cleft

  • CD8+ T-cells bind to MHC Class I - Endogenous Antigens

MHC Class II

  • Made of two alpha and two beta
  • Antigenic cleft is present in between Beta 1 and Alpha 1
  • Beta 1 and Alpha 1 are distal chains
  • MHC Class I is detected by Alloantiserum
  • MHC Class II is detected by Mixed Lymphpcyte Reaction
  • CD4+ T-cells bind to MHC Class II - Exogenous Antigens
  • Most antigens bind to MHC class II

Clinical Relevance Of MHC

  • Genetic Association of Disease
    • HLA - DR3/DR4 of class II region is associated with Type 1 Diabetes Melitus 3
    • HLA - B27 of Class I region is associated with Ankylosing spondytis 4
  • Organ Transplantation
    • Gene match of HLA is done to ensure compaitibility
    • Tissue typing is done by:
      • Mixed Lymphocyte Reaction (the same test for MHC II)
      • Micro-cytotoxicity assay
      • Nowadays HLA molecular matching is done
  • Paternity Disputes

T-Cell Activation

  • There are 2 signals involved
    • Primary Signal/Signal 1
      • MHC II binding to CD4 receptor
    • Co-stimulatory signal
      • CD28 on T cell with B7
        • B7a - CD80
        • B7b - CD86
    • Both signals are required for T-cell activation
      • External antigen provides both signals
      • Self antigens however only provide primary signal
        • Co-stimulatory signal is not generated - ANERGY
        • This property is known as: Tolerance is exhibited by Self-antigens ^248750
    • Negative co-stimulatory signal may also be received
      • Negative co-stimulatory signal delivery molecules - usually present in self-antigens
      • It reduces T-cell activation
        • CDLA-4
        • PD-1
      • B7.1 and B7.2 interact with this
      • This is another exhibition of Tolerance ^611163
Footnotes
1.
Antigen-dependent Cell-mediated Cytotoxicity - a type of cell-mediated immune response which involves both innate and adaptive components.Cells of innate immunity such as NK cell, eosinophils and neutrophils destroy the target cells which are coated with specific antibodies
2.
Major Histocompaitibility Complex
3.
Pancreas produces little to no insulin
4.
A type of arthritis in which there is a long-term inflammation of the joints of the spine. Typically the joints where the spine joins the pelvis are also affected. Occasionally other joints such as the shoulders or hips are involved. Eye and bowel problems may also occur. Back pain is a characteristic symptom of AS, and it often comes and goes. Stiffness of the affected joints generally worsens over time.
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