Introduction to the Immune System (The Immune System in Health and Disease) (Rheumatology) Part 6

Cellular Interactions in Regulation of Normal Immune Responses

The net result of activation of the humoral (B cell) and cellular (T cell) arms of the adaptive immune system by foreign antigen is the elimination of antigen directly by specific effector T cells or in concert with specific antibody. Figure 1-2 is a simplified schematic diagram of the T and B cell responses indicating some of these cellular interactions.

The expression of adaptive immune cell function is the result of a complex series of immunoregulatory events that occur in phases. Both T and B lymphocytes mediate immune functions, and each of these cell types, when given appropriate signals, passes through stages, from activation and induction through proliferation, differentiation, and ultimately effector functions. The effector function expressed may be at the end point of a response, such as secretion of antibody by a differentiated plasma cell, or it might serve a regulatory function that modulates other functions, such as is seen with CD4+ and CD8+ T lymphocytes that modulate both differentiation of B cells and activation of CD8+ cytotoxic T cells.

CD4 helper T cells can be subdivided on the basis of cytokines produced (Fig. 1-2).Activated TH1-type helper T cells secrete IL-2, IFN-γ, IL-3,TNF-a, GM-CSF, and TNF-ß, while activated TH2-type helper T cells secrete IL-3, -4, -5, -6, -10, and -13.TH1 CD4+ T cells, through elaboration of IFN-γ, have a central role in mediating intracellular killing by a variety of pathogens.TH1 CD4+ T cells also provide T cell help for generation of cytotoxic T cells and some types of opsonizing antibody, and they generally respond to antigens that lead to delayed hypersensitivity types of immune responses for many intracellular viruses and bacteria (such as HIV or M. tuberculosis). In contrast,TH2 cells have a primary role in regulatory humoral immunity and isotype switching. TH2 cells, through production of IL-4 and IL-10, have a regulatory role in limiting proinflammatory responses mediated by TH1 cells (Fig. 1-2). In addition, TH2 CD4+ T cells provide help to B cells for specific Ig production and respond to antigens that require high antibody levels for foreign antigen elimination (extracellular encapsulated bacteria such as Streptococcus pneumoniae and certain parasite infections). The type of T cell response generated in an immune response is determined by the microbe PAMPs presented to the dendritic cells, the TLRs on the dendritic cells that become activated, the types of dendritic cells that are activated, and the cytokines that are produced (Table 1-4). Commonly, myeloid dendritic cells produce IL-12 and activate TH1 T cell responses that result in IFN-γ and cytotoxic T cell induction, and plas-macytoid dendritic cells produce IFN-a and lead to TH2 responses that result in IL-4 production and enhanced antibody responses.

As shown in Figs. 1-2 and 1-3, upon activation by dendritic cells, T cell subsets that produce IL-2, IL-3, IFN-γ, and/or IL-4, -5, -6, -10, and -13 are generated and exert positive and negative influences on effector T and B cells. For B cells, trophic effects are mediated by a variety of cytokines, particularly T cell-derived IL-3, -4, -5, and -6, that act at sequential stages of B cell maturation, resulting in B cell proliferation, differentiation, and ultimately antibody secretion. For cytotoxic T cells, trophic factors include inducer T cell secretion of IL-2, IFN-γ, and IL-12.

An important type of immunomodulatory T cell that controls immune responses is CD4+ and CD8+ T regulatory cells. These cells constitutively express the a chain of the IL-2 receptor (CD25), produce large amounts of IL-10, and can suppress both T and B cell responses. T regulatory cells are induced by immature dendritic cells and play key roles in maintaining tolerance to selfantigens in the periphery. Loss of T regulatory cells is the cause of organ-specific autoimmune disease in mice such as autoimmune thyroiditis, adrenalitis, and oophoritis.T regulatory cells also play key roles in controlling the magnitude and duration of immune responses to microbes. Normally, after the initial immune response to a microbe has eliminated the invader, T regulatory cells are activated to suppress the antimicrobe response and prevent host injury. Some microbes have adapted to induce T regulatory cell activation at the site of infection to promote parasite infection and survival. In Leishmania infection, the parasite locally induces T regulatory cell accumulation at skin infection sites that dampens anti-Leishmania T cell responses and prevents elimination of the parasite. It is thought that many chronic infections such as by M. tuberculosis are associated with abnormal T regulatory cell activation that prevents elimination of the microbe.

Although B cells recognize native antigen via B cell surface Ig receptors, B cells require T cell help to produce high-affinity antibody of multiple isotypes that are the most effective in eliminating foreign antigen. This T cell dependence likely functions in the regulation of B cell responses and in protection against excessive autoantibody production. T cell-B cell interactions that lead to high-affinity antibody production require (1) processing of native antigen by B cells and expression of peptide fragments on the B cell surface for presentation to TH cells, (2) the ligation of B cells by both the TCR complex and the CD40 ligand, (3) induction of the process termed antibody isotype switching in antigen-specific B cell clones, and (4) induction of the process of affinity maturation of antibody in the germinal centers of B cell follicles of lymph node and spleen.

Naïve B cells express cell-surface IgD and IgM, and initial contact of naïve B cells with antigen is via binding of native antigen to B cell-surface IgM. T cell cytokines, released following TH2 cell contact with B cells or by a “bystander” effect, induce changes in Ig gene conformation that promote recombination of Ig genes. These events then result in the “switching” of expression of heavy chain exons in a triggered B cell, leading to the secretion of IgG, IgA, or, in some cases, IgE antibody with the same V region antigen specificity as the original IgM antibody, for response to a wide variety of extracellular bacteria, protozoa, and helminths. CD40 ligand expression by activated T cells is critical for induction of B cell antibody isotype switching and for B cell responsiveness to cytokines. Patients with mutations in T cell CD40 ligand have B cells that are unable to undergo isotype switching, resulting in lack of memory B cell generation and the immunodeficiency syndrome of X-linked hyper-IgM syndrome.

Immune Tolerance and Autoimmunity

Immune tolerance is defined as the absence of activation of pathogenic autoreactivity. Autoimmune diseases are syndromes caused by the activation of T or B cells or both, with no evidence of other causes such as infections or malignancies (Chap. 3). Once thought to be mutually exclusive, immune tolerance and autoimmunity are now both recognized to be present normally in health; when abnormal, they represent extremes from the normal state. For example, it is now known that low levels of autoreactivity of T and B cells with self-antigens in the periphery are critical to their survival. Similarly, low levels of autoreactivity and thymocyte recognition of selfantigens in the thymus are the mechanisms whereby (1) normal T cells are positively selected to survive and leave the thymus to respond to foreign microbes in the periphery, and (2) T cells highly reactive to self-antigens are negatively selected and die to prevent overly selfreactive T cells from getting into the periphery (central tolerance). However, not all self-antigens are expressed in the thymus to delete highly self-reactive T cells, and there are mechanisms for peripheral tolerance induction of T cells as well. Unlike the presentation of microbial antigens by mature dendritic cells, the presentation of self-antigens by immature dendritic cells neither activates nor matures the dendritic cells to express high levels of co-stimulatory molecules such as B7-1 (CD80) or B7-2 (CD86).When peripheral T cells are stimulated by dendritic cells expressing self-antigens in the context of HLA molecules, sufficient stimulation of T cells occurs to keep them alive, but otherwise they remain anergic, or nonresponsive, until they contact a dendritic cell with high levels of co-stimulatory molecules expressing microbial antigens. In the latter setting, normal T cells then become activated to respond to the microbe. If B cells have high-self-reactivity BCRs, they normally undergo receptor editing to express a less autoreactive receptor or are induced to die. Although many autoimmune diseases are characterized by abnormal or pathogenic autoantibody production (Table 1-12), most autoimmune diseases are caused by a combination of excess T and B cell reactivity.

Multiple factors contribute to the genesis of clinical autoimmune disease syndromes, including genetic susceptibility (Table 1-13), environmental immune stimulants such as drugs (e.g., procainamide and dilantin with drug-induced systemic lupus erythematosus), infectious agent triggers (such as Epstein-Barr virus and autoantibody production against red blood cells and platelets), and loss of T regulatory cells (leading to thyroiditis, adrenalitis, and oophoritis).

Immunity at Mucosal Surfaces

Mucosa covering the respiratory, digestive, and urogenital tracts; the eye conjunctiva; the inner ear; and the ducts of all exocrine glands contain cells of the innate and adaptive mucosal immune system that protect these surfaces against pathogens. In the healthy adult, mucosa-associated lymphoid tissue (MALT) contains 80% of all immune cells within the body and constitutes the largest mammalian lymphoid organ system.

MALT has three main functions: (1) to protect the mucous membranes from invasive pathogens; (2) to prevent uptake of foreign antigens from food, commensal organisms, and airborne pathogens and particulate matter; and (3) to prevent pathologic immune responses from foreign antigens if they do cross the mucosal barriers of the body.

MALT is a compartmentalized system of immune cells that functions independently from systemic immune organs. Whereas the systemic immune organs are essentially sterile under normal conditions and respond vigorously to pathogens, MALT immune cells are continuously bathed in foreign proteins and commensal bacteria, and they must select those pathogenic antigens that must be eliminated. MALT contains anatomically defined foci of immune cells in the intestine, tonsil, and peribronchial areas that are inductive sites for mucosal immune responses. From these sites immune T and B cells migrate to effector sites in mucosal parenchyma and exocrine glands where mucosal immune cells eliminate pathogen-infected cells. In addition to mucosal immune responses, all mucosal sites have strong mechanical and chemical barriers and cleansing functions to repel pathogens.

Key components of MALT include specialized epithelial cells called “membrane” or “M” cells that take up antigens and deliver them to dendritic cells or other APCs. Effector cells in MALT include B cells producing antipathogen neutralizing antibodies of secretory IgA as well as IgG isotype, T cells producing similar cytokines as in systemic immune system response, and T helper and cytotoxic T cells that respond to pathogen infected cells.

TABLE 1-12

RECOMBINANT OR PURIFIED AUTOANTIGENS RECOGNIZED BY AUTOANTIBODIES ASSOCIATED WITH HUMAN
AUTOIMMUNE DISORDERS
AUTOANTIGEN	AUTOIMMUNE DISEASES	AUTOANTIGEN	AUTOIMMUNE DISEASES
Cell- or Organ-Specific Autoimmunity
Acetylcholine receptor	Myasthenia gravis	Insulin receptor	Type B insulin resistance, acanthosis, systemic lupus erythematosus (SLE)
Actin	Chronic active hepatitis,
	primary bilary cirrhosis	Intrinsic factor type 1	Pernicious anemia
Adenine nucleotide translator (ANT)	Dilated cardiomyopathy, myocarditis	Leukocyte function-associated antigen	Treatment-resistant Lyme arthritis
ß-Adrenoreceptor	Dilated cardiomyopathy	(LFA-1)
Aromatic L-amino acid decarboxylase	Autoimmune polyendocrine syndrome type 1 (APS-1)	Myelin-associated glycoprotein (MAG)	Polyneuropathy
Asialoglycoprotein receptor	Autoimmune hepatitis	Myelin-basic protein	Multiple sclerosis, demyelinating diseases
Bactericidal/permeability-increasing protein (Bpi)	Cystic fibrosis vasculitides	Myelin oligodendrocyte glycoprotein (MOG)	Multiple sclerosis
Calcium-sensing receptor	Acquired hypoparathyroidism	Myosin	Rheumatic fever
Cholesterol side-chain cleavage enzyme (CYPlla)	Autoimmune polyglandular syndrome-1	p-80-Collin Pyruvate dehydrogenase	Atopic dermatitis Primary biliary cirrhosis
Collagen type IV-tó-chain	Goodpasture’s syndrome	complex-E2 (PDC-E2)
Cytochrome P450 2D6 (CYP2D6)	Autoimmune hepatitis	Sodium iodide symporter (NIS)	Graves’ disease, autoimmune hypothyroidism
Desmin	Crohn’s disease, coronary artery disease	S0X-10 Thyroid and eye muscle	Vitiligo Thyroid-associated ophthalmopathy
Desmoglein 1	Pemphigus foliaceus	shared protein
Desmoglein 3	Pemphigus vulgaris	Thyroglobulin	Autoimmune thyroiditis
F-actin	Autoimmune hepatitis	Thyroid peroxidase	Autoimmune Hashimoto thyroiditis
GM gangliosides	Guillain-Barré syndrome	Throtropin receptor	Graves’ disease
Glutamate decarboxylase	Type 1 diabetes, stiff man	Tissue transglutaminase	Celiac disease
(GAD65)	syndrome	Transcription	Atopic dermatitis
Glutamate receptor (GLUR)	Rasmussen encephalitis	coactivator p75
H/K ATPase	Autoimmune gastritis	Tryptophan hydroxylase	Autoimmune polyglandular
^nx-Hydroxylase (CYP17)	Autoimmune polyglandular		syndrome-1
	syndrome-1	Tyrosinase	Vitiligo, metastatic melanoma
21-Hydroxylase (CYP21) IA-2 (ICA512)	Addison’s disease Type 1 diabetes	Tyrosine hydroxylase	Autoimmune polyglandular syndrome-1
Insulin	Type 1 diabetes, insulin hypoglycemic syndrome (Hirata’s disease)
Systemic Autoimmunity
ACTH	ACTH deficiency	Histone H2A-H2B-DNA	SLE
Aminoacyl-tRAN histidyl synthetase	Myositis, dermatomyositis	IgE receptor	Chronic idiopathic urticaria
		Keratin	RA
Aminoacyl-tRNA synthetase (several)	Polymyositis, dermatomyositis	Ku-DNA-protein kinase	SLE
		Ku-nucleoprotein	Connective tissue syndrome
Cardiolipin	SLE, anti-phospholipid syndrome	La phosphoprotein (La 55-B)	Sjögren’s syndrome
Carbonic anhydrase II	SLE, Sjögren’s syndrome, systemic sclerosis	Myeloperoxidase	Necrotizing and crescentic glomerulonephritis (NCGN), systemic vasculitis
Collagen (multiple types)	Rheumatoid arthritis (RA), SLE, progressive systemic sclerosis	Proteinase 3 (PR3)
			Wegener granulomatosis, Churg-Strauss syndrome
Centromere-associated proteins	Systemic sclerosis

TABLE 1-12

RECOMBINANT OR PURIFIED AUTOANTIGENS RECOGNIZED BY AUTOANTIBODIES ASSOCIATED WITH HUMAN AUTOIMMUNE DISORDERS
AUTOANTIGEN	AUTOIMMUNE DISEASES	AUTOANTIGEN	AUTOIMMUNE DISEASES
Systemic Autoimmunity
DNA-dependent nucleosine-stimulated	Dermatomyositis	RNA polymerase I-III (RNP)	Systemic sclerosis, SLE
ATPase		Signal recognition protein (SRP54)	Polymyositis
Fibrillarin	Scleroderma
Fibronectin	SLE, RA, morphea	Topoisomerase-1 (Scl-70)	Scleroderma, Raynaud’s syndrome
Glucose-6-phosphate isomerase	RA	Tublin	Chronic liver disease, visceral leishmaniasis
ß2-Glycoprotein I (B2-GPI)	Primary antiphospholipid syndrome	Vimentin	Systemic autoimmune disease
Golgin (95, 97, 160, 180)	Sjögren’s syndrome, SLE, RA
Heat shock protein	Various immune-related disorders
Hemidesmosomal protein 180	Bullous pemphigoid, herpes gestationis, cicatricial pemphigoid
Plasma Protein and Cytokine Autoimmunity
C1 inhibitor	Autoimmune C1 deficiency	Glycoprotein IIb/IIIg and Ib/IX	Autoimmune thrombocytopenia purpura
C1q	SLE, membrane proliferative glomerulonephritis (MPGN)
		IgA	Immunodeficiency associated with SLE, pernicious anemia, thyroiditis, Sjögren’s syndrome and chronic active hepatitis
Cytokines (IL-1a, IL-1 ß, IL-6, IL-10, LIF)	RA, systemic sclerosis, normal subjects
Factor II, factor V factor VII, factor VIII, factor IX, factor X, factor XI, thrombin vWF	Prolonged coagulation time
		Oxidized LDL (OxLDL)	Atherosclerosis
Cancer and Paraneoplastic Autoimmunity
Amphiphysin	Neuropathy, small-cell lung cancer	p62 (IGF-II mRNA-binding protein)	Hepatocellular carcinoma (China)
Cyclin B1	Hepatocellular carcinoma	Recoverin	Cancer-associated retinopathy
DNA topoisomerase II	Liver cancer	Ri protein	Paraneoplastic opsoclonus myoclonus ataxia
Desmoplakin	Paraneoplastic pemphigus
Gephyrin	Paraneoplastic stiff man syndrome	ßIV spectrin	Lower motor neuron syndrome
		Synaptotagmin	Lambert-Eaton myasthenic syndrome
Hu proteins	Paraneoplastic encephalomyelitis
		Voltage-gated calcium channels	Lambert-Eaton myasthenic syndrome
Neuronal nicotinic acetylcholine receptor	Subacute autonomic neuropathy, cancer
		Yo protein	Paraneoplastic cerebellar degeneration
p53	Cancer, SLE

Secretory IgA is produced in amounts of >50 mg/kg of body weight per 24 h and functions to inhibit bacterial adhesion, inhibit macromolecule absorption in the gut, neutralize viruses, and enhance antigen elimination in tissue through binding to IgA and receptor-mediated transport of immune complexes through epithelial cells.

Recent studies have demonstrated the importance of commensal gut and other mucosal bacteria to the health of the human immune system. Normal commensal florainduces anti-inflammatory events in the gut and protects epithelial cells from pathogens through TLRs and other PRR signaling.

TABLE 1-13

IMMUNE SYSTEM MOLECULE DEFECTS IN ANIMALS OR HUMANS THAT CAUSE AUTOIMMUNE OR MALIGNANT SYNDROMES
PROTEIN	DEFECT	DISEASE OR SYNDROME	OBSERVATION IN ANIMAL MODELS OR HUMANS
Cytokines and Signaling Proteins
Tumor necrosis factor (TNF)-a	Overexpression	Inflammatory bowel disease (IBD), arthritis, vasculitis	Mice
TNF-a	Underexpression	Systemic lupus erythematosus (SLE)	Mice
Interleukin-1-receptor antagonist	Underexpression	Arthritis	Mice
IL-2	Overexpression	IBD	Mice
IL-7	Overexpression	IBD	Mice
IL-10	Overexpression	IBD	Mice
IL-2 receptor	Overexpression	IBD	Mice
IL-10 receptor	Overexpression	IBD	Mice
IL-3	Overexpression	Demyelinating syndrome	Mice
Interferon-δ	Overexpression in skin	SLE	Mice
STAT-3	Underexpression	IBD	Mice
STAT-4	Overexpression	IBD	Mice
Transforming growth factor (TGF)-ß	Underexpression	Systemic wasting syndrome and IBD	Mice
TGF-ß receptor in T cells	Underexpression	SLE	Mice
Programmed death (PD-1)	Underexpression	SLE-like syndrome	Mice
Cytotoxic T lymphocyte, antigen-4 (CTLA-4)	Underexpression	Systemic lymphoproliferative disease	Mice
IL-10	Underexpression	IBD (mouse) Type 1 diabetes, thyroid disease, primary (human)	Mice and humans
Major Histocompatibility Locus Moleculesa
HLA B27	Allele expression or overexpression	Inflammatory bowel disease	Rats and humans
Complement deficiency of C1, 2, 3, or 4	Underexpression		Humans
LIGHT (TNF superfamily 14)	Overexpression	Systemic lymphoproliferative (mouse) and autoimmunity	Mice
HLA class II DQB10301, DQB10302	Allele expression	Juvenile-onset diabetes	Human
HLA class II DQB10401, DQB10402	Allele expression	Rheumatoid arthritis	Humans
HLA class I B27	Allele expression	Ankylosing spondylitis, IBD	Rats and humans
Apoptosis Proteins
TNF receptor 1 (TNF-R1)	Underexpression	Familial periodic fever syndrome	Humans
Fas (CD95; Apo-1)	Underexpression	Autoimmune lymphoproliferative syndrome type 1 (ALPS 1); malignant lymphoma; bladder cancer	Humans
Fas ligand	Underexpression	SLE (only one case identified)	Humans
Perforin	Underexpression	Familial hemophagocytic lymphohistiocytosis (FHL)	Humans
Caspase 10	Underexpression	Autoimmune lymphoproliferative syndrome type II (ALPS II)	Humans
bcl-10	Underexpression	Non-Hodgkin’s lymphoma	Humans
P53	Underexpression	Various malignant neoplasms	Humans
Bax	Underexpression	Colon cancer; hematopoietic malignancies	Humans
bcl-2	Underexpression	Non-Hodgkin’s lymphoma	Humans
c-IAP2	Underexpression	Low-grade MALT lymphoma	Humans
NAIP1	Underexpression	Spinal muscular atrophy	Humans

^aMany autoimmune diseases are associated with a myriad of major compatibility complex gene allele (HLA) types. They are presented here as examples.

Note: MALT, mucosa-associated lymphoid tissue.

FIGURE 1-9

Increased epithelial permeability may be important in the development of chronic gut T cell-mediated inflammation. CD4 T cells activated by gut antigens in Peyer’s patches migrate to the LP In healthy individuals, these cells die by apoptosis. Increased epithelial permeability may allow sufficient antigen to enter the LP to trigger T cell activation, breaking tolerance mediated by immunosuppressive cytokines and perhaps T regulatory cells. Pro-inflammatory cytokines then further increase epithelial permeability, setting up a vicious cycle of chronic inflammation.

When the gut is depleted of normal commensal flora, the immune system becomes abnormal, with loss of TH1 T cell function. Restoration of the normal gut flora can reestablish the balance in T helper cell ratios characteristic of the normal immune system. When the gut barrier is intact, either antigens do not transverse the gut epithelium or, when pathogens are present, a self-limited, protective MALT immune response eliminates the pathogen (Fig. 1-9). However, when the gut barrier breaks down, immune responses to commensal flora antigens can cause inflammatory bowel diseases such as Crohn’s disease and, perhaps, ulcerative colitis (Fig. 1-9). Uncontrolled MALT immune responses to food antigens, such as gluten, can cause celiac disease.