eMedicine Specialties > Hematology > Stem Cells and Disorders

Mucosa-Associated Lymphoid Tissue

Author: Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Coauthor(s): Jose A Perez Jr, MD, MSEd, MBA, Consulting Physician, Department of Internal Medicine, Residency Director, Vice Chair of Education Department of Medicine, The Methodist Hospital, Houston; Associate Professor of Clinical Medicine, Weill Cornell Medical College
Contributor Information and Disclosures

Updated: Oct 14, 2008

Introduction

Background

A significant quantity of lymphoid tissue is associated with human mucosa. Mucosa-associated lymphoid tissue (MALT) is scattered along mucosal linings, measuring roughly 400 m2.1 2,3,4 It is the most extensive component of human lymphoid tissue. These surfaces protect the body from an enormous quantity and variety of antigens. The tonsils, Peyer patches within the small intestine, and the vermiform appendix are examples of mucosa-associated lymphoid tissue (MALT).

The nomenclature incorporates location; therefore, mucosa-associated lymphoid tissue (MALT) includes gut-associated lymphoid tissue (GALT), bronchial/tracheal-associated lymphoid tissue (BALT), nose-associated lymphoid tissue (NALT), and vulvovaginal-associated lymphoid tissue (VALT). Additional mucosa-associated lymphoid tissue (MALT) exists within the accessory organs of the digestive tract, predominantly the parotid gland.

Mucosa-associated lymphoid tissue (MALT) may consist of a collection of lymphoid cells, or it may include small solitary lymph nodes. Lymph nodes contain a light-staining region (germinal center) and a peripheral dark-staining region. The germinal center is key to the generation of a normal immune response. The location of mucosa-associated lymphoid tissue (MALT) is key to its function. Stimulation of B lymphocytes leads to the production of immunoglobulin A (IgA) and IgM within the Peyer patches, preventing adherence of bacteria and viruses to the epithelium, thus blocking entry to the subepithelial layers of the intestine.1,2,3,4,5

Mucosal epithelial surfaces contain M cells, which are specialized cells that are so named because they exhibit microfolds on their luminal surface and because of their membranous appearance. The role of the M cells is absorption, transport, processing, and presentation of antigens to subepithelial lymphoid cells.6,7 These subepithelial cells include CD4+ type 1 T-helper cells (THCs) and IgD/IgM+ B lymphocytes, the latter of which are antigen-presenting cells (APCs) and function as memory cells interacting with type 1 THCs.

Under these M cells and in close proximity, B lymphocytes, CD4+ T lymphocytes, and APCs are found, of which dendritic follicular cells (DFCs) are one type.8 Together, this group of cells constitutes a "pocket" of M cells. Within this pocket, an area of follicles associated with the epithelium (follicle-associated epithelium) is observed. These follicles, having true germinal centers, are similar to the follicles of the spleen and lymph nodes.

The direct secretion of secretory IgA onto mucosal epithelia represents the major effector mechanism of mucosa-associated lymphoid tissue (MALT). Major accumulations of lymphoid tissue are found in the lamina propria of the intestine. M cells in the intestinal epithelium overlying Peyer patches allow transport of antigens to the lymphoid tissue beneath it.

Another APC is the DFC, which activates some clones of type 1 THCs, although less potently than B lymphocytes. Stimulation of CD28 on type 1 THCs by B7 co-stimulatory molecules results in the secretion of interleukin 2 (IL-2) and gamma-interferon by type 1 THCs. Regulation of the immune response involves the suppression of type 2 THCs (involved in humoral immunity) by gamma-interferon and production of IL-10 by type 2 THCs, which inhibits type 1 THCs. Tolerance to antigens results from the lack of a T-lymphocyte response. Often, this is due to failed involvement of B-lymphocyte co-stimulatory molecules or cytokines. Signaling requires more than just receptor stimulation.

The activity of the germinal centers in the follicle-associated epithelium is key to the immune response. The germinal center provides an area where a large number of cells important in the immune response congregate. Early on in the T-cell–dependent immune response, B lymphocytes known as founder cells concentrate in the germinal center, forming the dark zone, where rapid division of these cells occurs.9,10,11,12

Selection of B lymphocytes for participation in the immune response occurs based on their interaction with antigen-antibody complexes on the surface of DFCs. This involves a series of steps that result in expression of complexes of major histocompatibility complex II (MHC II) and peptides resulting from processed antigens. This then begins a process of somatic hypermutation in the dark zone and, later, immunoglobulin class-switching and generation of memory cells and plasma cell precursors in the apical light zone of the germinal center.

The complex interplay among antigens, cells, and cytokines results in a very efficient immune response. The efficiency of mucosa-associated lymphoid tissue (MALT) also depends on the adequate function of IgA. Individuals with selective IgA deficiency are prone to infections along mucosal surfaces in the respiratory, gastrointestinal, and genitourinary tracts. Adequate function of IgA depends on the production and acquisition of a joining (J) chain. This glycoprotein is produced by plasma cells and is important in the formation of IgA dimers and IgM pentamers. It has been shown that in children who have recurrent tonsillitis, B lymphocytes in tonsillar crypts do not produce the J chain. The J chain is key in permitting secretory IgA and IgM to function as the first line of defense in mucosal epithelium.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

Pathophysiology

In selective IgA deficiency, the capability of the mucosal barrier is weakened and a second line of defense is activated. This consists of the participation and recruitment of large numbers of immune-competent cells, resulting in the onset of an inflammatory process that eradicates the antigen and restores functionality to the mucosa. If this process is constant and intense, it may result in a chronic inflammatory process.

Malignancies that occur in mucosa-associated lymphoid tissue (MALT) are called MALT lymphomas or MALTomas. MALTomas are extranodal manifestations of marginal-zone lymphomas. Most MALTomas are a low grade, although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most of the MALTomas occur in the stomach, and roughly 70% of gastric MALTomas are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(11;18). The specific gene abnormalities responsible for the pathogenesis of MALTomas have not yet been identified. Mutations commonly identified in NHLs are not commonly present in MALTomas, although both BCL2 and TP53 have been reported.

Frequency

United States

MALTomas account for approximately 5% of NHLs diagnosed annually. NHL represents only 4% of non–skin cancer malignancies.

International

NHL accounts for 2-3% of all malignancies, and MALTomas comprise approximately 5% of all NHLs. Although extensive studies have not been performed, no particular ethnic group or geographic area shows a strong predilection for MALTomas.

Mortality/Morbidity

  • Morbidity and mortality occur when neoplastic transformation into a MALToma develops.
  • Most MALTomas are responsive to available treatment modalities, including radiation and chemotherapy. In addition, H. pylori – associated tumors may respond to antibiotics.13
  • The most common morbidities associated with gastrointestinal MALTomas include abdominal pain, gastrointestinal bleeding, and gastrointestinal obstruction. Gastric or intestinal perforation is rare.

Race

No significant racial differences of mucosa-associated lymphoid tissue (MALT) distribution are known; however, some epidemiologic studies indicate a slight increase in MALTomas in whites relative to blacks.

Sex

Although no sex differences are known regarding mucosa-associated lymphoid tissue (MALT) distribution, males usually have a more extensive distribution of lymphoid tissue. However, according to some epidemiologic studies, MALTomas are slightly more common in females than in males.

Age

The peak incidence of MALTomas is during the seventh and eighth decades of life. However, MALTomas have been noted in children, adolescents, and young adults.

Clinical

History

The median age of onset of MALTomas is 65 years. According to some epidemiologic studies, MALTomas are slightly more common in females than in males and are more common in whites than in blacks.

  • Symptoms of MALTomas are nonspecific and are related to the organs involved.
    • Gastric MALToma symptoms may mimic peptic ulcer disease or gastritis.
    • Chronic fatigue, low-grade fevers, nausea, constipation, tarry stool, epigastric pain, weight loss, anemia, and shortness of breath are some of the more nonspecific symptoms that may occur in patients with gastric MALTomas.
    • Recurrent respiratory infections may be observed in some patients, especially in patients with pulmonary MALTomas.
    • Patients with conjunctival MALTomas may present with blurry vision or visual-field defects.
    • Patients with MALTomas often have a history of an associated autoimmune disease.

Physical

Most patients with MALTomas have no physical findings; lymphadenopathy is rare.

Causes

Although the cause of MALTomas and most other tumors is still unknown, accumulated evidence indicates a strong association between autoimmune diseases and MALTomas. A clear causal association exists between H. pylori infection and gastric MALTomas.

  • Continued massive antigen stimulation is postulated to represent a critical step in the development and progression of MALTomas.
  • MALTomas of the salivary glands are often associated with Sjogren syndrome.
  • MALTomas of the thyroid are associated with Hashimoto thyroiditis.
  • Crohn disease or celiac disease may be involved in the genesis of intestinal MALTomas.
  • In contrast to weaker etiologic associations, infection with H. pylori has been definitively established as a cause of MALTomas. H. pylori gastritis is common in individuals who develop gastric lymphomas.

More on Mucosa-Associated Lymphoid Tissue

Overview: Mucosa-Associated Lymphoid Tissue
Differential Diagnoses & Workup: Mucosa-Associated Lymphoid Tissue
Treatment & Medication: Mucosa-Associated Lymphoid Tissue
Follow-up: Mucosa-Associated Lymphoid Tissue
References
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Further Reading

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Keywords

mucosa-associated lymphoid tissue, lymphoid tissue, MALToma, MALT lymphoma, MALT, marginal zone B-cell lymphoma, lymph node, mucus membrane, mucus, mucosal tissue, tonsils, Peyer patches, Peyer's patches, vermiform appendix, non-Hodgkin lymphoma, non-Hodgkin's lymphoma, NHL, lymphoma, malignancy, malignancies, cancer, Hashimoto thyroiditis, Hashimoto's thyroiditis, Crohn disease, Crohn's disease, celiac disease, Sjögren syndrome,
gut-associated lymphoid tissue, GALT, bronchial/tracheal-associated lymphoid tissue, BALT, nose-associated lymphoid tissue, NALT, vulvovaginal-associated lymphoid tissue, VALT, gastric MALT lymphoma, nongastric MALT lymphoma, gastric MALToma, nongastric MALToma, human mucosa

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Contributor Information and Disclosures

Author

Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Sara J Grethlein, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Jose A Perez Jr, MD, MSEd, MBA, Consulting Physician, Department of Internal Medicine, Residency Director, Vice Chair of Education Department of Medicine, The Methodist Hospital, Houston; Associate Professor of Clinical Medicine, Weill Cornell Medical College
Jose A Perez Jr, MD, MSEd, MBA is a member of the following medical societies: American College of Physician Executives, American College of Physicians, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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